Is ENG p.Ser635Leu (c.1904C>T) pathogenic?

ENG p.Ser635Leu (c.1904C>T) is classified Uncertain significance in ENG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-10). AlphaMissense: ambiguous (0.4226); Ultra-rare (popmax 0.0204%, afr); Associated with ENG-related disorder.

What condition is associated with ENG p.Ser635Leu (c.1904C>T)?

ENG p.Ser635Leu (c.1904C>T) is associated with ENG-related disorder (ClinVar).

How common is ENG p.Ser635Leu (c.1904C>T) in the general population?

ENG p.Ser635Leu (c.1904C>T) is ultra-rare (popmax 0.0204%, afr) (gnomAD).

What do computational predictors say about ENG p.Ser635Leu (c.1904C>T)?

AlphaMissense predicts ambiguous (score 0.4226) — an in-silico prediction, not a clinical call.

ENG p.Ser635Leu

c.1904C>T · rs758012489 · VCV1782359

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4226 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ENG-related disorder

Computational evidence

Protein change
AlphaMissense	0.4226	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -7.19	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.92, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	29.9	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 0.0204% African / African-American · 15/73,364 alleles

Filtering AF 0.0125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00271% 42/1,547,440 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0204%	4,891
South Asian	0.0142%	7,025
Finnishnot grpmax-eligible	0.00378%	26,427
East Asian	0.00242%	41,276
European (non-Finnish)	0.00104%	95,795

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.Ser635Leu
Coding: c.1904C>T
MANE Select: NM_001114753
dbSNP: rs758012489
Type: single nucleotide variant
Location: chr9:127815755 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 635: the 'disordered' region

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

Disease context

ENG-related disorder

Similar variants

ENG p.Ser635= Likely benign ★ same residue
ENG c.1686+1G>A Pathogenic ★★ same condition
ENG c.-127C>T Pathogenic/Likely pathogenic ★★ same condition
ENG p.Arg171Ter Pathogenic ★★ same condition
ENG p.Cys242Ter Pathogenic ★★ same condition
ENG p.Gln508Ter Pathogenic ★★ same condition
ENG p.Gln87Ter Pathogenic ★★ same condition
ENG p.Gly501Ter 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-ser635leu (accessed [today's date]).

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