Is RIN2 p.Ser124Tyr (c.371C>A) pathogenic?

RIN2 p.Ser124Tyr (c.371C>A) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-15). AlphaMissense: ambiguous (0.4947); Very rare (popmax 0.00298%, nfe).

How common is RIN2 p.Ser124Tyr (c.371C>A) in the general population?

RIN2 p.Ser124Tyr (c.371C>A) is very rare (popmax 0.00298%, nfe) (gnomAD).

What do computational predictors say about RIN2 p.Ser124Tyr (c.371C>A)?

AlphaMissense predicts ambiguous (score 0.4947) — an in-silico prediction, not a clinical call.

RIN2 p.Ser124Tyr

c.371C>A · rs1433693137 · VCV2012476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4947 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00298%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4947	ambiguous
REVEL	0.404	indeterminate
SaProt	LLR -14.27	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	27.7	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 0.00298% European (non-Finnish) · 35/1,173,020 alleles

Filtering AF 0.00217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00192%

Overall 0.00225% 36/1,599,740 alleles · very rare exomes 35/1,447,530 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00298%	33,515
Remaining individualsnot grpmax-eligible	0.00161%	62,034

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: RIN2
Protein: p.Ser124Tyr
Coding: c.371C>A
MANE Select: NM_018993
dbSNP: rs1433693137
Type: single nucleotide variant
Location: chr20:19960719 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 124: the sh2 domain

Full RIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RASSF4 p.Ser124Leu Uncertain significance ★ ⚠ same residue
RIN2 p.Ala205Val Uncertain significance ★★ ⚠ same type
RIN2 p.Ala72Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Ala8Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Arg135Cys Uncertain significance ★★ ⚠ same type
RIN2 p.Arg170Trp Uncertain significance ★★ ⚠ same type
RIN2 p.Arg255Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Arg290Leu 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/rin2-p-ser124tyr (accessed [today's date]).

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