Is ENG p.Cys53Ser (c.158G>C) pathogenic?

ENG p.Cys53Ser (c.158G>C) is classified Uncertain significance in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-27). AlphaMissense: likely pathogenic (0.9423); Absent from gnomAD v4.1.

How common is ENG p.Cys53Ser (c.158G>C) in the general population?

ENG p.Cys53Ser (c.158G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENG p.Cys53Ser (c.158G>C)?

AlphaMissense predicts likely pathogenic (score 0.9423) — an in-silico prediction, not a clinical call.

ENG p.Cys53Ser

c.158G>C · rs187643086 · VCV439663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9423 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9423	likely pathogenic · top 3% in ENG
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -14.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ENG
Protein: p.Cys53Ser
Coding: c.158G>C
MANE Select: NM_001114753
dbSNP: rs187643086
Type: single nucleotide variant
Location: chr9:127843155 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 53: a disulfide bond; a UniProt-annotated variant site (in hht1; impairs protein folding; abolishes expression at the cell surface); the 'required for interaction with gdf2' region; the 'or2' region; a β-strand

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

Similar variants

ENG p.Cys53Arg Pathogenic/Likely pathogenic ★★ same residue
ENG p.Cys53Ter Pathogenic ★★ same residue
ENG p.Cys53= Benign/Likely benign ★★ same residue
ENG p.Cys53Tyr Likely benign ★ ⚠ same residue
ENG p.Arg529His Pathogenic ★★★ ⚠ same type
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same type
ENG p.Cys382Tyr Pathogenic ★★★ same type
ENG p.Cys549Gly Likely pathogenic ★★★ same type

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-cys53ser (accessed [today's date]).

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