Is ENG p.Ser634Ala (c.1900T>G) pathogenic?

ENG p.Ser634Ala (c.1900T>G) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-21). AlphaMissense: likely benign (0.0886); Very rare (popmax 0.000871%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Ser634Ala (c.1900T>G)?

ENG p.Ser634Ala (c.1900T>G) is associated with Cardiovascular phenotype (ClinVar).

How common is ENG p.Ser634Ala (c.1900T>G) in the general population?

ENG p.Ser634Ala (c.1900T>G) is very rare (popmax 0.000871%, nfe) (gnomAD).

What do computational predictors say about ENG p.Ser634Ala (c.1900T>G)?

AlphaMissense predicts likely benign (score 0.0886) — an in-silico prediction, not a clinical call.

ENG p.Ser634Ala

c.1900T>G · rs1040594389 · VCV1782310

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000871%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

ClinGen expert panel — Hereditary Hemorrhagic Telangiectasia VCEP

Uncertain Significance for telangiectasia, hereditary hemorrhagic, type 1. Applied ACMG criteria (verbatim):

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_001114753.3: c.1900T>G variant in ENG is a missense variant predicted to cause substitution of serine by alanine at amino acid 634 (p.Ser634Ala). This variant has not been observed in gnomAD v2.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.158, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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: PM2_Supporting (specifications version 1.1.0; 04/10/2026).

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

Computational evidence

Protein change
AlphaMissense	0.0886	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -7.10	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 7.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	22.4	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 0.000871% European (non-Finnish) · 10/1,148,656 alleles

Filtering AF 0.00044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000321%

Overall 0.000647% 10/1,546,022 alleles · very rare

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.Ser634Ala
Coding: c.1900T>G
MANE Select: NM_001114753
dbSNP: rs1040594389
Type: single nucleotide variant
Location: chr9:127815759 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 634: the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ENG p.Ser634Phe Uncertain significance ★ ⚠ same residue
ENG p.Ser634= Likely benign ★ same residue
ENG c.1134+1G>T Pathogenic/Likely pathogenic ★★ same condition
ENG c.1311+2T>A Pathogenic ★★ same condition
ENG c.1428+1G>A Pathogenic/Likely pathogenic ★★ same condition
ENG c.1687-1G>A Pathogenic/Likely pathogenic ★★ same condition
ENG c.219+1G>A Pathogenic ★★ same condition
ENG c.219+2T>C Pathogenic/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-ser634ala (accessed [today's date]).

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