Is RINT1 p.Cys478Phe (c.1433G>T) pathogenic?

RINT1 p.Cys478Phe (c.1433G>T) is classified Uncertain significance in RINT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.8585); Ultra-rare (popmax 0.0168%, amr).

How common is RINT1 p.Cys478Phe (c.1433G>T) in the general population?

RINT1 p.Cys478Phe (c.1433G>T) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about RINT1 p.Cys478Phe (c.1433G>T)?

AlphaMissense predicts likely pathogenic (score 0.8585) — an in-silico prediction, not a clinical call.

RINT1 p.Cys478Phe

c.1433G>T · rs377454711 · VCV963608

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8585	likely pathogenic
REVEL	0.492	indeterminate
SaProt	LLR -11.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 3.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 35 kb · p 0.28 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0168% Admixed American · 10/59,604 alleles

Filtering AF 0.00905% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00685%

Overall 0.00124% 20/1,611,488 alleles · ultra-rare exomes 16/1,459,286 · genomes 4/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,960
African / African-American	0.00134%	74,850
European (non-Finnish)	0.000763%	130,976

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: RINT1
Protein: p.Cys478Phe
Coding: c.1433G>T
MANE Select: NM_021930
dbSNP: rs377454711
Type: single nucleotide variant
Location: chr7:105551669 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.97
Residue 478: the rint1/tip20 domain

Full RINT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RINT1 p.Cys478Arg Uncertain significance ★ ⚠ same residue
RINT1 p.Cys478Tyr Uncertain significance ★ ⚠ same residue
RINT1 c.1107+1G>T Likely pathogenic ★★ same type
RINT1 c.1886+5G>A Uncertain significance ★★ same type
RINT1 c.516-3C>T Uncertain significance ★★ same type
RINT1 c.840-12T>A Uncertain significance ★★ same type
RINT1 c.840-3C>G Uncertain significance ★★ same type
RINT1 p.Ala138Thr 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/rint1-p-cys478phe (accessed [today's date]).

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