Is EXT1 p.Val454Ile (c.1360G>A) pathogenic?

EXT1 p.Val454Ile (c.1360G>A) is classified Likely benign in EXT1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-21). AlphaMissense: likely benign (0.0794); Ultra-rare (popmax 0.0661%, mid); Associated with exostoses, multiple, type 1.

What condition is associated with EXT1 p.Val454Ile (c.1360G>A)?

EXT1 p.Val454Ile (c.1360G>A) is associated with exostoses, multiple, type 1, hereditary multiple osteochondromas (ClinVar).

How common is EXT1 p.Val454Ile (c.1360G>A) in the general population?

EXT1 p.Val454Ile (c.1360G>A) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

How is Multiple osteochondromas inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EXT1 p.Val454Ile (c.1360G>A)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

EXT1 p.Val454Ile

c.1360G>A · rs201504622 · VCV134200

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

exostoses, multiple, type 1

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -4.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	21.8	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 0.0661% Middle Eastern · 4/6,056 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00403% 65/1,613,266 alleles · ultra-rare exomes 59/1,460,996 · genomes 6/152,270 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,514
African / African-American	0.0227%	4,413
Remaining individualsnot grpmax-eligible	0.0064%	15,620
East Asian	0.00446%	22,424
South Asian	0.00439%	22,769
Admixed American	0.00333%	30,012
European (non-Finnish)	0.00271%	36,861

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.Val454Ile
Coding: c.1360G>A
MANE Select: NM_000127
dbSNP: rs201504622
Type: single nucleotide variant
Location: chr8:117822522 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB

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

Disease context

exostoses, multiple, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary multiple osteochondromas

For Multiple osteochondromas (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: >1 / 1000 (Specific population)

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-val454ile (accessed [today's date]).

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