Is ENG p.Arg232Gly (c.694C>G) pathogenic?

ENG p.Arg232Gly (c.694C>G) is classified Uncertain significance in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-28). AlphaMissense: likely benign (0.1823); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ENG p.Arg232Gly (c.694C>G)?

ENG p.Arg232Gly (c.694C>G) is associated with Cardiovascular phenotype (ClinVar).

How common is ENG p.Arg232Gly (c.694C>G) in the general population?

ENG p.Arg232Gly (c.694C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ENG p.Arg232Gly (c.694C>G)?

AlphaMissense predicts likely benign (score 0.1823) — an in-silico prediction, not a clinical call.

ENG p.Arg232Gly

c.694C>G · VCV4836916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1823	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -5.44	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 -1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00223% East Asian · 1/44,786 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000822% 12/1,459,992 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,786
Admixed American	0.00168%	59,562
European (non-Finnish)	0.000848%	117,956

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.Arg232Gly
Coding: c.694C>G
MANE Select: NM_001114753
Type: single nucleotide variant
Location: chr9:127825353 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 232: a β-strand; a UniProt-annotated variant site (in hht1); the 'required for interaction with gdf2' region; the 'or1, c-terminal part' 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.Arg232_Thr233del Likely pathogenic ★★ same residue
ENG p.Arg232Leu Uncertain significance ★ ⚠ same residue
ENG p.Arg232Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
ENG p.Arg232Gln 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

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-arg232gly (accessed [today's date]).

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