Is INTS1 p.Arg1657Cys (c.4969C>T) pathogenic?

INTS1 p.Arg1657Cys (c.4969C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-06). AlphaMissense: likely benign (0.2372); Rare (popmax 0.215%, mid); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

What condition is associated with INTS1 p.Arg1657Cys (c.4969C>T)?

INTS1 p.Arg1657Cys (c.4969C>T) is associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Arg1657Cys (c.4969C>T) in the general population?

INTS1 p.Arg1657Cys (c.4969C>T) is rare (popmax 0.215%, mid) (gnomAD).

What do computational predictors say about INTS1 p.Arg1657Cys (c.4969C>T)?

AlphaMissense predicts likely benign (score 0.2372) — an in-silico prediction, not a clinical call.

INTS1 p.Arg1657Cys

c.4969C>T · rs760923660 · VCV1804946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2372 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.215%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.2372	likely benign
REVEL	0.489	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Pangolin	Δ0.21	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.6	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.001 · regional, not allelic
Overall
CADD	24.7	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 0.215% Middle Eastern · 13/6,052 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.00726% 117/1,612,092 alleles · rare exomes 107/1,459,882 · genomes 10/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.215%	466
Admixed American	0.0184%	5,447
Remaining individualsnot grpmax-eligible	0.0176%	5,675
European (non-Finnish)	0.00636%	15,729
East Asian	0.00446%	22,438
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,580
African / African-American	0.00267%	37,453
South Asian	0.0022%	45,487

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.Arg1657Cys
Coding: c.4969C>T
MANE Select: NM_001080453
dbSNP: rs760923660
Type: single nucleotide variant
Location: chr7:1476888 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB
Residue 1657: an α-helix

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

Disease context

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS1 p.Arg1657His Uncertain significance ★★ ⚠ 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.Ala745Thr Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1130Cys Uncertain significance ★★ ⚠ same condition
INTS1 p.Arg1685Gln 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-arg1657cys (accessed [today's date]).

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