Is RIN1 p.Val129Ile (c.385G>A) pathogenic?

RIN1 p.Val129Ile (c.385G>A) is classified Likely benign in RIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely benign (0.069); Ultra-rare (popmax 0.0104%, nfe).

How common is RIN1 p.Val129Ile (c.385G>A) in the general population?

RIN1 p.Val129Ile (c.385G>A) is ultra-rare (popmax 0.0104%, nfe) (gnomAD).

What do computational predictors say about RIN1 p.Val129Ile (c.385G>A)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

RIN1 p.Val129Ile

c.385G>A · VCV4154497

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0104%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -8.57	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 -8.7	GERP -2.8
Regional constraint	o/e 0.98	unconstrained · MANE · 4,123 bp · p 0.45 · regional, not allelic
Overall
CADD	1.045	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 0.0104% European (non-Finnish) · 123/1,179,732 alleles

Filtering AF 0.00893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00836%

Overall 0.00886% 143/1,613,342 alleles · ultra-rare exomes 129/1,461,072 · genomes 14/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0104%	9,591
African / African-American	0.00933%	10,718
Remaining individualsnot grpmax-eligible	0.0064%	15,620
South Asian	0.0055%	18,175
East Asian	0.00446%	22,422
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,560
Admixed American	0.00167%	59,892

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: RIN1
Protein: p.Val129Ile
Coding: c.385G>A
MANE Select: NM_004292
Type: single nucleotide variant
Location: chr11:66335680 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.78
Residue 129: the sh2 domain

Full RIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIN1 p.Ala690= Benign ★★ same type
RIN1 p.Gly737= Benign ★★ same type
RIN1 p.Thr643= Benign/Likely benign ★★ same type
RIN1 p.Val700Ile Benign ★★ same type
RIN1 p.Ala111Thr Uncertain significance ★ ⚠ same type
RIN1 p.Ala168Thr Uncertain significance ★ ⚠ same type
RIN1 p.Ala221Ser Uncertain significance ★ ⚠ same type
RIN1 p.Ala31Val 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/rin1-p-val129ile (accessed [today's date]).

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