Is EXT1 p.Val292Phe (c.874G>T) pathogenic?

EXT1 p.Val292Phe (c.874G>T) is classified Conflicting classifications of pathogenicity in EXT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-03-03). AlphaMissense: likely pathogenic (0.6256); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with EXT1 p.Val292Phe (c.874G>T)?

EXT1 p.Val292Phe (c.874G>T) is associated with Inborn genetic diseases, hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Val292Phe (c.874G>T) in the general population?

EXT1 p.Val292Phe (c.874G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EXT1 p.Val292Phe (c.874G>T)?

AlphaMissense predicts likely pathogenic (score 0.6256) — an in-silico prediction, not a clinical call.

EXT1 p.Val292Phe

c.874G>T · rs1586279359 · VCV644948

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6256 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6256	likely pathogenic
REVEL	0.616	indeterminate
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 3.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 280 kb · p 4.8e-06 · 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 0.00133% African / African-American · 1/75,068 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,196 alleles · very rare exomes 6/1,461,884 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,068
European (non-Finnish)	0.000424%	236,008

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.Val292Phe
Coding: c.874G>T
MANE Select: NM_000127
dbSNP: rs1586279359
Type: single nucleotide variant
Location: chr8:118110173 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 292: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary multiple osteochondromas

Similar variants

EXT1 p.Val292Ala Uncertain significance ★ ⚠ same residue
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

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-val292phe (accessed [today's date]).

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