Is RIN2 p.Pro349Ser (c.1045C>T) pathogenic?

RIN2 p.Pro349Ser (c.1045C>T) is classified Conflicting classifications of pathogenicity in RIN2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0713); Rare (popmax 0.262%, amr); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Pro349Ser (c.1045C>T)?

RIN2 p.Pro349Ser (c.1045C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Pro349Ser (c.1045C>T) in the general population?

RIN2 p.Pro349Ser (c.1045C>T) is rare (popmax 0.262%, amr) (gnomAD).

What do computational predictors say about RIN2 p.Pro349Ser (c.1045C>T)?

AlphaMissense predicts likely benign (score 0.0713) — an in-silico prediction, not a clinical call.

RIN2 p.Pro349Ser

c.1045C>T · rs201486809 · VCV436540

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0713 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.262%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0713	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP 2, phastCons 0.96
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	19.05	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 0.262% Admixed American · 157/60,016 alleles

Filtering AF 0.228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.215%

Overall 0.111% 1,799/1,613,520 alleles · rare exomes 1,653/1,461,232 · genomes 146/152,288 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.262%	382
Remaining individualsnot grpmax-eligible	0.131%	762
European (non-Finnish)	0.131%	766
Middle Eastern	0.0165%	6,062
Finnishnot grpmax-eligible	0.0126%	7,945
African / African-American	0.012%	8,340
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: RIN2
Protein: p.Pro349Ser
Coding: c.1045C>T
MANE Select: NM_018993
dbSNP: rs201486809
Type: single nucleotide variant
Location: chr20:19975070 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 349: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIN2 p.Pro349Leu Uncertain significance ★ ⚠ same residue
RIN2 p.Ala205Val Uncertain significance ★★ ⚠ same condition
RIN2 p.Ala72Thr Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg135Cys Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg170Trp Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg255Thr Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg290Leu Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg303Gln Uncertain significance ★★ ⚠ 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/rin2-p-pro349ser (accessed [today's date]).

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