Is RINT1 p.Ser40Cys (c.118A>T) pathogenic?

RINT1 p.Ser40Cys (c.118A>T) is classified Benign in RINT1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0723); Common (popmax 25.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with infantile liver failure syndrome 3.

What condition is associated with RINT1 p.Ser40Cys (c.118A>T)?

RINT1 p.Ser40Cys (c.118A>T) is associated with infantile liver failure syndrome 3 (ClinVar).

What do computational predictors say about RINT1 p.Ser40Cys (c.118A>T)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

RINT1 p.Ser40Cys

Q: How common is RINT1 p.Ser40Cys (c.118A>T) in the general population?

RINT1 p.Ser40Cys (c.118A>T) is common (popmax 25.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.118A>T · rs11556986 · VCV403377

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 25.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile liver failure syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.68, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 35 kb · p 0.28 · regional, not allelic
Overall
CADD	16.9	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 25.1% African / African-American · 18,673/74,360 alleles

Filtering AF 24.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.7%

Overall 18% 287,910/1,598,734 alleles · common exomes 257,681/1,446,574 · genomes 30,229/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	25.1%	4
South Asian	25%	4
Middle Eastern	21.7%	5
Admixed American	19.2%	5
Ashkenazi Jewishnot grpmax-eligible	19%	5
Finnishnot grpmax-eligible	18.9%	5
Remaining individualsnot grpmax-eligible	18.5%	5
European (non-Finnish)	17.5%	6
Amishnot grpmax-eligible	11.9%	8
East Asian	1.62%	62

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.Ser40Cys
Coding: c.118A>T
MANE Select: NM_021930
dbSNP: rs11556986
Type: single nucleotide variant
Location: chr7:105536594 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 85.97
Residue 40: a UniProt-annotated variant site (in)

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.Ser40= Likely benign ★ same residue
RINT1 p.Ser40Asn Likely benign ★ 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-ser40cys (accessed [today's date]).

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