Is INTS11 p.Val515Met (c.1543G>A) pathogenic?

INTS11 p.Val515Met (c.1543G>A) is classified Uncertain significance in INTS11 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-09). AlphaMissense: likely benign (0.2946); Ultra-rare (popmax 0.0243%, eas); Associated with neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities.

How common is INTS11 p.Val515Met (c.1543G>A) in the general population?

INTS11 p.Val515Met (c.1543G>A) is ultra-rare (popmax 0.0243%, eas) (gnomAD).

What do computational predictors say about INTS11 p.Val515Met (c.1543G>A)?

AlphaMissense predicts likely benign (score 0.2946) — an in-silico prediction, not a clinical call.

INTS11 p.Val515Met

Q: What condition is associated with INTS11 p.Val515Met (c.1543G>A)?

INTS11 p.Val515Met (c.1543G>A) is associated with neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (ClinVar).

c.1543G>A · rs747481892 · VCV2506981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2946 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.2946	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -13.32	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 13 kb · p 0.087 · regional, not allelic
Overall
CADD	25.3	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 0.0243% East Asian · 10/41,232 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00998%

Overall 0.00439% 68/1,549,026 alleles · ultra-rare exomes 60/1,398,382 · genomes 8/150,644 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0243%	4,123
Remaining individualsnot grpmax-eligible	0.00666%	15,006
European (non-Finnish)	0.00453%	22,056
Admixed American	0.00197%	50,780
African / African-American	0.00137%	72,968

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.Val515Met
Coding: c.1543G>A
MANE Select: NM_017871
dbSNP: rs747481892
Type: single nucleotide variant
Location: chr1:1312290 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.82 · 15 PDB
Residue 515: a β-strand; a UniProt-annotated variant site (in nedmlob; uncertain significance; may affect function; the orthologous mutation in ints11-deficient drosophila is unable to rescue locomotor defects)

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

Disease context

neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INTS11 c.28+1406C>T Uncertain significance ★★ same condition
INTS11 p.Arg231Cys Uncertain significance ★★ ⚠ same condition
INTS11 p.Glu227Lys Uncertain significance ★★ same condition
INTS11 c.1738-1G>A Likely pathogenic ★ same condition
INTS11 p.Arg17Leu Pathogenic ★ same condition
INTS11 p.Arg43Ter Pathogenic ★ same condition
INTS11 p.Glu554Gly Uncertain significance ★ ⚠ same condition
INTS11 p.Gly455Ser 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/ints11-p-val515met (accessed [today's date]).

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