Is RINT1 p.Leu447Phe (c.1339C>T) pathogenic?

RINT1 p.Leu447Phe (c.1339C>T) is classified Uncertain significance in RINT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-22). AlphaMissense: ambiguous (0.3409); Very rare (popmax 0.00225%, eas); Associated with infantile liver failure syndrome 3.

What condition is associated with RINT1 p.Leu447Phe (c.1339C>T)?

RINT1 p.Leu447Phe (c.1339C>T) is associated with infantile liver failure syndrome 3 (ClinVar).

How common is RINT1 p.Leu447Phe (c.1339C>T) in the general population?

RINT1 p.Leu447Phe (c.1339C>T) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about RINT1 p.Leu447Phe (c.1339C>T)?

AlphaMissense predicts ambiguous (score 0.3409) — an in-silico prediction, not a clinical call.

RINT1 p.Leu447Phe

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.1339C>T · rs1562851056 · VCV1001996

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3409 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

infantile liver failure syndrome 3

Computational evidence

Protein change
AlphaMissense	0.3409	ambiguous
REVEL	0.192	benign-leaning
SaProt	LLR -7.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6	GERP 3.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 35 kb · p 0.28 · regional, not allelic
Overall
CADD	32.0	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 0.00225% East Asian · 1/44,368 alleles

Overall 0.000125% 2/1,596,256 alleles · very rare exomes 2/1,443,996 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,368
African / African-American	0.00134%	74,366

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.Leu447Phe
Coding: c.1339C>T
MANE Select: NM_021930
dbSNP: rs1562851056
Type: single nucleotide variant
Location: chr7:105551575 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.97
Residue 447: 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.Leu447Val 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-leu447phe (accessed [today's date]).

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