Is INTS1 p.Ala688Val (c.2063C>T) pathogenic?

INTS1 p.Ala688Val (c.2063C>T) is classified Uncertain significance in INTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-19). AlphaMissense: likely benign (0.1932); Very rare (popmax 0.0047%, eas); Associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies.

What condition is associated with INTS1 p.Ala688Val (c.2063C>T)?

INTS1 p.Ala688Val (c.2063C>T) is associated with neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies (ClinVar).

How common is INTS1 p.Ala688Val (c.2063C>T) in the general population?

INTS1 p.Ala688Val (c.2063C>T) is very rare (popmax 0.0047%, eas) (gnomAD).

What do computational predictors say about INTS1 p.Ala688Val (c.2063C>T)?

AlphaMissense predicts likely benign (score 0.1932) — an in-silico prediction, not a clinical call.

INTS1 p.Ala688Val

c.2063C>T · VCV4056797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0047%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.1932	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.59	donor gain · deltas
Pangolin	Δ0.33	gain · loss 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.12 · regional, not allelic
Overall
CADD	30.0	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 0.0047% East Asian · 2/42,522 alleles

Filtering AF 0.00089% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000728%

Overall 0.00152% 24/1,577,298 alleles · very rare exomes 23/1,425,108 · genomes 1/152,190 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0047%	21,261
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,944
South Asian	0.00233%	42,957
Admixed American	0.00183%	54,552
Remaining individualsnot grpmax-eligible	0.00164%	61,162
European (non-Finnish)	0.00146%	68,423

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.Ala688Val
Coding: c.2063C>T
MANE Select: NM_001080453
Type: single nucleotide variant
Location: chr7:1493759 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.49 · 8 PDB

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 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
INTS1 p.Arg1800Gln 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-ala688val (accessed [today's date]).

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