Is RINT1 p.Pro419Arg (c.1256C>G) pathogenic?

RINT1 p.Pro419Arg (c.1256C>G) is classified Conflicting classifications of pathogenicity in RINT1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-23). AlphaMissense: likely benign (0.1411); Ultra-rare (popmax 0.0188%, nfe); Associated with infantile liver failure syndrome 3.

What condition is associated with RINT1 p.Pro419Arg (c.1256C>G)?

RINT1 p.Pro419Arg (c.1256C>G) is associated with infantile liver failure syndrome 3 (ClinVar).

How common is RINT1 p.Pro419Arg (c.1256C>G) in the general population?

RINT1 p.Pro419Arg (c.1256C>G) is ultra-rare (popmax 0.0188%, nfe) (gnomAD).

What do computational predictors say about RINT1 p.Pro419Arg (c.1256C>G)?

AlphaMissense predicts likely benign (score 0.1411) — an in-silico prediction, not a clinical call.

RINT1 p.Pro419Arg

Q: How is Fever-associated acute infantile liver failure syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1256C>G · rs374836052 · VCV659053

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1411 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile liver failure syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1411	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -11.62	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 3.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 35 kb · p 0.28 · regional, not allelic
Overall
CADD	24.7	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 0.0188% European (non-Finnish) · 222/1,180,016 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.0141% 227/1,613,996 alleles · ultra-rare exomes 216/1,461,856 · genomes 11/152,140 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0188%	5,315
African / African-American	0.004%	24,971
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Pro419Arg
Coding: c.1256C>G
MANE Select: NM_021930
dbSNP: rs374836052
Type: single nucleotide variant
Location: chr7:105550409 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.97
Residue 419: the rint1/tip20 domain

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

Disease context

infantile liver failure syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fever-associated acute infantile liver failure syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

RINT1 p.Pro419Ser Uncertain significance ★ ⚠ same residue
RINT1 c.840-12T>A Uncertain significance ★★ same condition
RINT1 p.Arg374Trp Uncertain significance ★★ same condition
RINT1 p.Asp477His Uncertain significance ★★ ⚠ same condition
RINT1 p.Cys537Arg Uncertain significance ★★ ⚠ same condition
RINT1 p.His613Asn Uncertain significance ★★ ⚠ same condition
RINT1 p.Leu107Val Uncertain significance ★★ ⚠ same condition
RINT1 p.Leu406Ile 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/rint1-p-pro419arg (accessed [today's date]).

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