Is RIN2 p.Pro220Ala (c.658C>G) pathogenic?

RIN2 p.Pro220Ala (c.658C>G) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-14). AlphaMissense: likely benign (0.0685); Ultra-rare (popmax 0.011%, sas).

How common is RIN2 p.Pro220Ala (c.658C>G) in the general population?

RIN2 p.Pro220Ala (c.658C>G) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about RIN2 p.Pro220Ala (c.658C>G)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

RIN2 p.Pro220Ala

c.658C>G · rs780665287 · VCV1950261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 2.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	18.25	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,076 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00198% 32/1,613,542 alleles · ultra-rare exomes 30/1,461,372 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0048%	20,818
European (non-Finnish)	0.00161%	62,086

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.Pro220Ala
Coding: c.658C>G
MANE Select: NM_018993
dbSNP: rs780665287
Type: single nucleotide variant
Location: chr20:19974683 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30

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-pro220ala (accessed [today's date]).

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