Is INTS11 p.Ala498Thr (c.1492G>A) pathogenic?

INTS11 p.Ala498Thr (c.1492G>A) is classified Uncertain significance in INTS11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.5654); Very rare (popmax 0.00356%, nfe).

How common is INTS11 p.Ala498Thr (c.1492G>A) in the general population?

INTS11 p.Ala498Thr (c.1492G>A) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about INTS11 p.Ala498Thr (c.1492G>A)?

AlphaMissense predicts likely pathogenic (score 0.5654) — an in-silico prediction, not a clinical call.

INTS11 p.Ala498Thr

c.1492G>A · VCV4275894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5654	likely pathogenic
REVEL	0.17	moderately benign-leaning
SaProt	LLR -9.22	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.087 · regional, not allelic
Overall
CADD	25.0	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 0.00356% European (non-Finnish) · 41/1,152,902 alleles

Filtering AF 0.00264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00238%

Overall 0.00269% 42/1,561,344 alleles · very rare exomes 41/1,409,186 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,120
Remaining individualsnot grpmax-eligible	0.00165%	60,518

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: INTS11
Protein: p.Ala498Thr
Coding: c.1492G>A
MANE Select: NM_017871
Type: single nucleotide variant
Location: chr1:1312341 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.82 · 15 PDB
Residue 498: an α-helix

Full INTS11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INTS11 c.28+1406C>T Uncertain significance ★★ same type
INTS11 p.Ala241Thr Uncertain significance ★★ ⚠ same type
INTS11 p.Arg231Cys Uncertain significance ★★ ⚠ same type
INTS11 p.Gln467His Uncertain significance ★★ ⚠ same type
INTS11 p.Glu227Lys Uncertain significance ★★ same type
INTS11 p.His157Arg Uncertain significance ★★ ⚠ same type
INTS11 c.1607+18C>A Benign ★★ same type
INTS11 p.Arg196= Benign ★★ same type

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/ints11-p-ala498thr (accessed [today's date]).

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