Is EXT2 p.Trp396Ser (c.1187G>C) pathogenic?

EXT2 p.Trp396Ser (c.1187G>C) is classified Uncertain significance in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-18). AlphaMissense: likely pathogenic (0.5756); Very rare (popmax 0.00653%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXT2 p.Trp396Ser (c.1187G>C)?

EXT2 p.Trp396Ser (c.1187G>C) is associated with Inborn genetic diseases, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Trp396Ser (c.1187G>C) in the general population?

EXT2 p.Trp396Ser (c.1187G>C) is very rare (popmax 0.00653%, nfe) (gnomAD).

What do computational predictors say about EXT2 p.Trp396Ser (c.1187G>C)?

AlphaMissense predicts likely pathogenic (score 0.5756) — an in-silico prediction, not a clinical call.

EXT2 p.Trp396Ser

c.1187G>C · rs750542485 · VCV2893003

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5756	likely pathogenic
REVEL	0.758	pathogenic-leaning
SaProt	LLR -13.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00653% European (non-Finnish) · 77/1,180,028 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.00496% 80/1,613,984 alleles · very rare exomes 77/1,461,874 · genomes 3/152,110 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00653%	15,325
African / African-American	0.00267%	37,456
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: EXT2
Protein: p.Trp396Ser
Coding: c.1187G>C
MANE Select: NM_207122
dbSNP: rs750542485
Type: single nucleotide variant
Location: chr11:44171624 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 396: an α-helix

Full EXT2 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: exostoses, multiple, type 2

Similar variants

EXT2 p.Trp396Leu Uncertain significance ★★ ⚠ same residue
EXT2 p.Trp396Ter Pathogenic ★ same residue
EXT2 p.Trp396fs Pathogenic ★ same residue
EXT2 c.1079+1G>A Pathogenic ★★ same condition
EXT2 c.1079+1G>T Pathogenic ★★ same condition
EXT2 c.1173+1G>A Pathogenic ★★ same condition
EXT2 c.1662+1G>C Likely pathogenic ★★ same condition
EXT2 c.536+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/ext2-p-trp396ser (accessed [today's date]).

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