Is EXT1 p.Asp399Val (c.1196A>T) pathogenic?

EXT1 p.Asp399Val (c.1196A>T) is classified Conflicting classifications of pathogenicity in EXT1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-01-30). AlphaMissense: likely pathogenic (0.5903); Very rare (popmax 0.00446%, eas); Associated with ovarian cancer.

What condition is associated with EXT1 p.Asp399Val (c.1196A>T)?

EXT1 p.Asp399Val (c.1196A>T) is associated with ovarian cancer, hereditary multiple osteochondromas, chondrosarcoma (ClinVar).

How common is EXT1 p.Asp399Val (c.1196A>T) in the general population?

EXT1 p.Asp399Val (c.1196A>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about EXT1 p.Asp399Val (c.1196A>T)?

AlphaMissense predicts likely pathogenic (score 0.5903) — an in-silico prediction, not a clinical call.

EXT1 p.Asp399Val

c.1196A>T · rs1275929525 · VCV2445286

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.5903	likely pathogenic
REVEL	0.529	indeterminate
SaProt	LLR -11.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.39	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · 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 0.00446% East Asian · 2/44,870 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000434% 7/1,613,976 alleles · very rare exomes 6/1,461,738 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,435
European (non-Finnish)	0.000424%	235,998

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: EXT1
Protein: p.Asp399Val
Coding: c.1196A>T
MANE Select: NM_000127
dbSNP: rs1275929525
Type: single nucleotide variant
Location: chr8:117830318 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 399: an α-helix

Full EXT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary multiple osteochondromas chondrosarcoma

Similar variants

EXT1 c.1056+1G>A Pathogenic ★★ same condition
EXT1 c.1056+1G>T Pathogenic ★★ same condition
EXT1 c.1165-1G>A Pathogenic ★★ same condition
EXT1 c.1285-1G>C Pathogenic ★★ same condition
EXT1 c.1417+1G>A Pathogenic ★★ same condition
EXT1 c.1417+1G>T Pathogenic ★★ same condition
EXT1 c.1418-1G>A Pathogenic ★★ same condition
EXT1 c.1418-2A>G Pathogenic ★★ 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/ext1-p-asp399val (accessed [today's date]).

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