Is RIN2 p.Pro143Ser (c.427C>T) pathogenic?

RIN2 p.Pro143Ser (c.427C>T) is classified Benign in RIN2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0924); Low-frequency (popmax 1.3%, nfe).

How common is RIN2 p.Pro143Ser (c.427C>T) in the general population?

RIN2 p.Pro143Ser (c.427C>T) is low-frequency (popmax 1.3%, nfe) (gnomAD).

What do computational predictors say about RIN2 p.Pro143Ser (c.427C>T)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

RIN2 p.Pro143Ser

c.427C>T · rs45488002 · VCV389389

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.3%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.08	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 2.2	GERP 0.47, phastCons 0.92
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	12.19	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 1.3% European (non-Finnish) · 15,295/1,174,216 alleles

Filtering AF 1.29% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.28%

Overall 1.1% 17,579/1,601,884 alleles · low-frequency exomes 16,150/1,449,622 · genomes 1,429/152,262 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.3%	77
Finnishnot grpmax-eligible	1.21%	83
Remaining individualsnot grpmax-eligible	0.894%	112
Ashkenazi Jewishnot grpmax-eligible	0.806%	124
Admixed American	0.743%	135
Middle Eastern	0.661%	151
African / African-American	0.183%	546
South Asian	0.128%	780
East Asian	0.00899%	11,129

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.Pro143Ser
Coding: c.427C>T
MANE Select: NM_018993
dbSNP: rs45488002
Type: single nucleotide variant
Location: chr20:19960775 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 143: the sh2 domain

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

Similar variants

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
RIN2 p.Arg303Gln 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-pro143ser (accessed [today's date]).

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