Is ENG p.Ala628Val (c.1883C>T) pathogenic?

ENG p.Ala628Val (c.1883C>T) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-23). AlphaMissense: likely benign (0.2054); Ultra-rare (popmax 0.0616%, mid); Associated with telangiectasia, hereditary hemorrhagic, type 1.

What condition is associated with ENG p.Ala628Val (c.1883C>T)?

ENG p.Ala628Val (c.1883C>T) is associated with telangiectasia, hereditary hemorrhagic, type 1 (ClinVar).

How common is ENG p.Ala628Val (c.1883C>T) in the general population?

ENG p.Ala628Val (c.1883C>T) is ultra-rare (popmax 0.0616%, mid) (gnomAD).

How is Hereditary hemorrhagic telangiectasia inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ENG p.Ala628Val (c.1883C>T)?

AlphaMissense predicts likely benign (score 0.2054) — an in-silico prediction, not a clinical call.

ENG p.Ala628Val

c.1883C>T · rs757113987 · VCV1781928

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0616%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

telangiectasia, hereditary hemorrhagic, type 1

ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP

Likely Benign for telangiectasia, hereditary hemorrhagic, type 1. Applied ACMG criteria (verbatim):

BP5 BP4

Curation rationale (ClinGen, verbatim)

The NM_001114753.3: c.1883C>T variant in ENG is a missense variant predicted to cause substitution of alanine by valine at amino acid 628 (p.Ala628Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007858 (2/25452 alleles) in the Admixed American population. The computational predictor REVEL gives a score of 0.145, which is below the threshold of ≤0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). This variant has been observed in a patient with an alternate molecular basis for disease (pathogenic variant identified in ACVRL1) (BP5; internal lab contributors). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BP4, BP5 (specifications version 1.1.0; 04/10/2026).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.2054	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0616% Middle Eastern · 3/4,870 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00892%

Overall 0.00375% 58/1,545,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0616%	1,623
African / African-American	0.0082%	12,197
South Asian	0.00476%	21,011
Admixed American	0.00392%	25,518
European (non-Finnish)	0.00366%	27,318
Remaining individualsnot grpmax-eligible	0.00167%	59,962

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ENG
Protein: p.Ala628Val
Coding: c.1883C>T
MANE Select: NM_001114753
dbSNP: rs757113987
Type: single nucleotide variant
Location: chr9:127815776 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 628: the 'disordered' region

Full ENG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

telangiectasia, hereditary hemorrhagic, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hemorrhagic telangiectasia (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ENG p.Ala628= Likely benign ★ same residue
ENG p.Arg529His Pathogenic ★★★ same condition
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same condition
ENG p.Cys382Tyr Pathogenic ★★★ same condition
ENG p.Cys549Gly Likely pathogenic ★★★ same condition
ENG p.Gly331Ser Pathogenic ★★★ ⚠ same condition
ENG p.Gly603Arg Likely pathogenic ★★★ same condition
ENG p.Leu221Pro Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/eng-p-ala628val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown