Is ENG p.Thr135Asn (c.404C>A) pathogenic?

ENG p.Thr135Asn (c.404C>A) is classified Conflicting classifications of pathogenicity in ENG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-05-14). AlphaMissense: likely benign (0.1258); Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Thr135Asn (c.404C>A)?

ENG p.Thr135Asn (c.404C>A) is associated with Cardiovascular phenotype, hereditary hemorrhagic telangiectasia (ClinVar).

How common is ENG p.Thr135Asn (c.404C>A) in the general population?

ENG p.Thr135Asn (c.404C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ENG p.Thr135Asn (c.404C>A)?

AlphaMissense predicts likely benign (score 0.1258) — an in-silico prediction, not a clinical call.

ENG p.Thr135Asn

c.404C>A · VCV4798755

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1258	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -9.91	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 -3.6	GERP -4.1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	0.019	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 0.00267% African / African-American · 2/74,908 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,454
South Asian	0.0011%	91,090
European (non-Finnish)	8.47e-05%	1,180,036

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.Thr135Asn
Coding: c.404C>A
MANE Select: NM_001114753
Type: single nucleotide variant
Location: chr9:127826629 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 135: a β-strand; a disulfide bond; the 'required for interaction with gdf2' region; the 'or2' 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

Also linked: hereditary hemorrhagic telangiectasia

Similar variants

ENG p.Thr135= Conflicting classifications of pathogenicity ★ same residue
ENG p.Thr135Ile Uncertain significance ★ ⚠ 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

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-thr135asn (accessed [today's date]).

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