Is RIN2 p.Ala643Thr (c.1927G>A) pathogenic?

RIN2 p.Ala643Thr (c.1927G>A) is classified Benign in RIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0797); Low-frequency (popmax 2.24%, afr).

How common is RIN2 p.Ala643Thr (c.1927G>A) in the general population?

RIN2 p.Ala643Thr (c.1927G>A) is low-frequency (popmax 2.24%, afr) (gnomAD).

What do computational predictors say about RIN2 p.Ala643Thr (c.1927G>A)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

RIN2 p.Ala643Thr

c.1927G>A · rs199603 · VCV506448

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.24%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -4.60	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 7.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 241 bp · p 0.45 · regional, not allelic
Overall
CADD	22.3	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 2.24% African / African-American · 1,680/74,916 alleles

Filtering AF 2.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.12%

Overall 0.118% 1,896/1,604,702 alleles · low-frequency exomes 911/1,452,382 · genomes 985/152,320 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.24%	45
Admixed American	0.156%	641
Remaining individualsnot grpmax-eligible	0.129%	777
Middle Eastern	0.0495%	2,019
East Asian	0.0224%	4,458
South Asian	0.00337%	29,715
European (non-Finnish)	0.00247%	40,546

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.Ala643Thr
Coding: c.1927G>A
MANE Select: NM_018993
dbSNP: rs199603
Type: single nucleotide variant
Location: chr20:19990170 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 643: a UniProt-annotated variant site (in); the vps9 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-ala643thr (accessed [today's date]).

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