Is RIN2 p.Pro577Ser (c.1729C>T) pathogenic?

RIN2 p.Pro577Ser (c.1729C>T) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.7061); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Pro577Ser (c.1729C>T)?

RIN2 p.Pro577Ser (c.1729C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Pro577Ser (c.1729C>T) in the general population?

RIN2 p.Pro577Ser (c.1729C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about RIN2 p.Pro577Ser (c.1729C>T)?

AlphaMissense predicts likely pathogenic (score 0.7061) — an in-silico prediction, not a clinical call.

RIN2 p.Pro577Ser

c.1729C>T · rs756703809 · VCV1917971

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7061 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7061	likely pathogenic
REVEL	0.13	moderately benign-leaning
SaProt	LLR -5.51	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 7.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 14 kb · p 0.49 · regional, not allelic
Overall
CADD	26.0	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 0.00334% Admixed American · 2/59,860 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,612,154 alleles · very rare exomes 4/1,459,850 · genomes 0/152,304 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,930
African / African-American	0.00133%	75,012
European (non-Finnish)	8.48e-05%	1,179,268

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.Pro577Ser
Coding: c.1729C>T
MANE Select: NM_018993
dbSNP: rs756703809
Type: single nucleotide variant
Location: chr20:19975754 (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

Disease context

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

Similar variants

RIN2 p.Pro577Ala Uncertain significance ★ ⚠ same residue
RIN2 p.Pro577= Likely benign ★ 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

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-pro577ser (accessed [today's date]).

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