Is EXT1 p.Ala486Val (c.1457C>T) pathogenic?

EXT1 p.Ala486Val (c.1457C>T) is classified Benign in EXT1 (ClinVar, Single submitter, 4 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0898); Rare (popmax 0.345%, eas); Associated with hereditary multiple osteochondromas.

What condition is associated with EXT1 p.Ala486Val (c.1457C>T)?

EXT1 p.Ala486Val (c.1457C>T) is associated with hereditary multiple osteochondromas, microcephaly (ClinVar).

How common is EXT1 p.Ala486Val (c.1457C>T) in the general population?

EXT1 p.Ala486Val (c.1457C>T) is rare (popmax 0.345%, eas) (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.Ala486Val (c.1457C>T)?

AlphaMissense predicts likely benign (score 0.0898) — an in-silico prediction, not a clinical call.

EXT1 p.Ala486Val

c.1457C>T · rs188859975 · VCV134202

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0898 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.345%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary multiple osteochondromas

Computational evidence

Protein change
AlphaMissense	0.0898	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.25 · regional, not allelic
Overall
CADD	23.2	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 0.345% East Asian · 155/44,876 alleles

Filtering AF 0.301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.284%

Overall 0.0108% 174/1,613,412 alleles · rare exomes 156/1,461,128 · genomes 18/152,284 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.345%	290
Remaining individualsnot grpmax-eligible	0.00801%	12,490
South Asian	0.00439%	22,762
Admixed American	0.00333%	30,009
African / African-American	0.00267%	37,508
European (non-Finnish)	0.000508%	196,667

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.Ala486Val
Coding: c.1457C>T
MANE Select: NM_000127
dbSNP: rs188859975
Type: single nucleotide variant
Location: chr8:117819755 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 486: a β-strand; a UniProt-annotated variant site (in ext1; no effect on heparan sulfate proteoglycan biosynthetic process)

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

Disease context

hereditary multiple osteochondromas — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microcephaly

For Multiple osteochondromas (Orphanet):

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

Similar variants

EXT1 p.Ala486= Conflicting classifications of pathogenicity ★ 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-ala486val (accessed [today's date]).

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