Is ECT2 p.Arg381His (c.1142G>A) pathogenic?

ECT2 p.Arg381His (c.1142G>A) is classified Uncertain significance in ECT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: ambiguous (0.4331); Ultra-rare (popmax 0.0783%, amr).

How common is ECT2 p.Arg381His (c.1142G>A) in the general population?

ECT2 p.Arg381His (c.1142G>A) is ultra-rare (popmax 0.0783%, amr) (gnomAD).

What do computational predictors say about ECT2 p.Arg381His (c.1142G>A)?

AlphaMissense predicts ambiguous (score 0.4331) — an in-silico prediction, not a clinical call.

ECT2 p.Arg381His

c.1142G>A · rs747643442 · VCV3087096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4331 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0783%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4331	ambiguous
REVEL	0.657	pathogenic-leaning
SaProt	LLR -7.88	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 66 kb · p 1.6e-05 · regional, not allelic
Overall
CADD	27.5	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 0.0783% Admixed American · 47/59,996 alleles

Filtering AF 0.0604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00421% 68/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0783%	1,277
Middle Eastern	0.0164%	6,084
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,868
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,904
European (non-Finnish)	0.00119%	84,286
South Asian	0.0011%	91,088

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: ECT2
Protein: p.Arg381His
Coding: c.1142G>A
MANE Select: NM_001258315
dbSNP: rs747643442
Type: single nucleotide variant
Location: chr3:172764351 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.17 · 3 PDB

Full ECT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECT2 p.His912Arg Uncertain significance ★★ ⚠ same type
ECT2 p.Pro236Ala Uncertain significance ★★ ⚠ same type
ECT2 p.Pro481= Benign ★★ same type
ECT2 c.1069-2A>G Uncertain significance ★ same type
ECT2 p.Ala258Thr Uncertain significance ★ ⚠ same type
ECT2 p.Ala850Thr Uncertain significance ★ ⚠ same type
ECT2 p.Arg169Cys Uncertain significance ★ ⚠ same type
ECT2 p.Arg194Met 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/ect2-p-arg381his (accessed [today's date]).

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