Is ENG p.Ser140Pro (c.418T>C) pathogenic?

ENG p.Ser140Pro (c.418T>C) is classified Likely benign in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0603); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Ser140Pro (c.418T>C)?

ENG p.Ser140Pro (c.418T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is ENG p.Ser140Pro (c.418T>C) in the general population?

ENG p.Ser140Pro (c.418T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ENG p.Ser140Pro (c.418T>C)?

AlphaMissense predicts likely benign (score 0.0603) — an in-silico prediction, not a clinical call.

ENG p.Ser140Pro

c.418T>C · VCV4843439

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0603	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.07	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 -4.6	GERP -4.1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	0.009	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 0.000169% European (non-Finnish) · 2/1,180,006 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,936 alleles · very rare exomes 1/1,461,840 · genomes 1/152,096 · joint denominator

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.Ser140Pro
Coding: c.418T>C
MANE Select: NM_001114753
Type: single nucleotide variant
Location: chr9:127826615 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 140: 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

Similar variants

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
ENG c.360+1G>A Pathogenic ★★ same condition
ENG c.360+1G>C 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-ser140pro (accessed [today's date]).

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