Is INTS1 p.Arg77Cys (c.229C>T) pathogenic?

INTS1 p.Arg77Cys (c.229C>T) is classified Conflicting classifications of pathogenicity in INTS1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-08-21). AlphaMissense: likely pathogenic (0.8862); Ultra-rare (popmax 0.0817%, amr); Associated with Inborn genetic diseases.

What condition is associated with INTS1 p.Arg77Cys (c.229C>T)?

INTS1 p.Arg77Cys (c.229C>T) is associated with Inborn genetic diseases, neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Arg77Cys (c.229C>T) in the general population?

INTS1 p.Arg77Cys (c.229C>T) is ultra-rare (popmax 0.0817%, amr) (gnomAD).

What do computational predictors say about INTS1 p.Arg77Cys (c.229C>T)?

AlphaMissense predicts likely pathogenic (score 0.8862) — an in-silico prediction, not a clinical call.

INTS1 p.Arg77Cys

c.229C>T · rs200649090 · VCV689521

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8862 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0817%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8862	likely pathogenic
REVEL	0.207	benign-leaning
SaProt	LLR -11.60	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	33.0	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 0.0817% Admixed American · 49/60,012 alleles

Filtering AF 0.0634% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.057%

Overall 0.0083% 134/1,613,702 alleles · ultra-rare exomes 129/1,461,482 · genomes 5/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0817%	1,225
European (non-Finnish)	0.00678%	14,749
African / African-American	0.00267%	37,467
Remaining individualsnot grpmax-eligible	0.0016%	62,458
Finnishnot grpmax-eligible	0.00157%	63,828
South Asian	0.0011%	91,088

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: INTS1
Protein: p.Arg77Cys
Coding: c.229C>T
MANE Select: NM_001080453
dbSNP: rs200649090
Type: single nucleotide variant
Location: chr7:1503021 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 77: a UniProt-annotated variant site (in ndcagf; uncertain significance)

Full INTS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Similar variants

INTS1 p.Arg77His Conflicting classifications of pathogenicity ★ ⚠ same residue
INTS1 c.3430-2A>C Likely pathogenic ★★ same condition
INTS1 p.Arg101Ter Likely pathogenic ★★ same condition
INTS1 c.1283+5G>A Uncertain significance ★★ same condition
INTS1 c.2977-5C>T Uncertain significance ★★ same condition
INTS1 p.Ala1505Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala1854Val Uncertain significance ★★ ⚠ same condition
INTS1 p.Ala2155Val 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/ints1-p-arg77cys (accessed [today's date]).

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