Is EXT2 p.Val305Phe (c.913G>T) pathogenic?

EXT2 p.Val305Phe (c.913G>T) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: likely benign (0.1082); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXT2 p.Val305Phe (c.913G>T)?

EXT2 p.Val305Phe (c.913G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXT2 p.Val305Phe (c.913G>T) in the general population?

EXT2 p.Val305Phe (c.913G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about EXT2 p.Val305Phe (c.913G>T)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

EXT2 p.Val305Phe

c.913G>T · VCV4252116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.662	pathogenic-leaning
SaProt	LLR -9.16	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	21.9	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 0.00167% Admixed American · 1/60,004 alleles

Overall 6.2e-05% 1/1,613,240 alleles · very rare exomes 1/1,461,038 · genomes 0/152,202 · joint denominator

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.Val305Phe
Coding: c.913G>T
MANE Select: NM_207122
Type: single nucleotide variant
Location: chr11:44124958 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 305: a β-strand

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

Similar variants

EXT2 p.Val305Leu Uncertain significance ★ ⚠ same residue
EXT2 p.Gly277Ter Pathogenic ★★ same condition
EXT2 p.Ala171Glu Uncertain significance ★★ ⚠ same condition
EXT2 p.Ala458Thr Uncertain significance ★★ ⚠ same condition
EXT2 p.Ala630Pro Uncertain significance ★★ ⚠ same condition
EXT2 p.Arg10Gln Uncertain significance ★★ ⚠ same condition
EXT2 p.Arg17Thr Uncertain significance ★★ ⚠ same condition
EXT2 p.Arg23Gln Uncertain significance ★★ ⚠ 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-val305phe (accessed [today's date]).

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