Is ECE2 p.Arg379His (c.1136G>A) pathogenic?

ECE2 p.Arg379His (c.1136G>A) is classified Likely benign in ECE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely benign (0.059); Very rare (popmax 0.00533%, afr).

How common is ECE2 p.Arg379His (c.1136G>A) in the general population?

ECE2 p.Arg379His (c.1136G>A) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about ECE2 p.Arg379His (c.1136G>A)?

AlphaMissense predicts likely benign (score 0.059) — an in-silico prediction, not a clinical call.

ECE2 p.Arg379His

c.1136G>A · VCV3506425

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.059	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -8.82	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 0.005	GERP -3.4, phastCons 0.06
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.014 · regional, not allelic
Overall
CADD	1.704	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R425H vs ClinVar R379H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,044 alleles

Filtering AF 0.00174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00285% 46/1,613,886 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,931
Remaining individualsnot grpmax-eligible	0.0096%	10,416
African / African-Americangrpmax	0.00533%	18,761
East Asian	0.00446%	22,441
Admixed American	0.00333%	29,998
European (non-Finnish)	0.0022%	45,379

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ECE2
Protein: p.Arg379His
Coding: c.1136G>A
MANE Select: NM_001100121
Type: single nucleotide variant
Location: chr3:184285093 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 379: a disulfide bond; the peptidase m13 domain

Full ECE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECE2 p.Arg379Cys Uncertain significance ★ ⚠ same residue
ECE2 p.Arg379Leu Uncertain significance ★ ⚠ same residue
ECE2 p.Arg453Gln Benign ★★ same type
ECE2 p.Ser400= Benign ★★ same type
ECE2 p.Val248= Benign ★★ same type
EEF1AKMT4-ECE2 p.Val127Ala Benign ★★ same type
ECE2 p.Ala338Val Uncertain significance ★ ⚠ same type
ECE2 p.Ala437Thr Uncertain significance ★ ⚠ 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/ece2-p-arg379his (accessed [today's date]).

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