Is RINT1 p.Ser586Ala (c.1756T>G) pathogenic?

RINT1 p.Ser586Ala (c.1756T>G) is classified Uncertain significance in RINT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0775); Ultra-rare (popmax 0.035%, amr); Associated with infantile liver failure syndrome 3.

What condition is associated with RINT1 p.Ser586Ala (c.1756T>G)?

RINT1 p.Ser586Ala (c.1756T>G) is associated with infantile liver failure syndrome 3 (ClinVar).

How common is RINT1 p.Ser586Ala (c.1756T>G) in the general population?

RINT1 p.Ser586Ala (c.1756T>G) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about RINT1 p.Ser586Ala (c.1756T>G)?

AlphaMissense predicts likely benign (score 0.0775) — an in-silico prediction, not a clinical call.

RINT1 p.Ser586Ala

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.1756T>G · rs552354215 · VCV410809

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0775 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile liver failure syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0775	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP 3.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 35 kb · p 0.28 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.035% Admixed American · 21/60,018 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00341% 55/1,613,906 alleles · ultra-rare exomes 32/1,461,560 · genomes 23/152,346 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,858
African / African-American	0.00533%	18,763
Remaining individualsnot grpmax-eligible	0.0048%	20,833
European (non-Finnish)	0.00229%	43,694

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.Ser586Ala
Coding: c.1756T>G
MANE Select: NM_021930
dbSNP: rs552354215
Type: single nucleotide variant
Location: chr7:105563817 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.97
Residue 586: 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.Ser586Cys Uncertain significance ★★ ⚠ same residue
RINT1 p.Ser586Thr 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

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-ser586ala (accessed [today's date]).

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