Is EXT2 p.Phe400Leu (c.1200C>A) pathogenic?

EXT2 p.Phe400Leu (c.1200C>A) is classified Benign in EXT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-08). AlphaMissense: likely pathogenic (0.9184); Ultra-rare (popmax 0.0535%, eas); Associated with ovarian cancer.

What condition is associated with EXT2 p.Phe400Leu (c.1200C>A)?

EXT2 p.Phe400Leu (c.1200C>A) is associated with ovarian cancer, exostoses, multiple, type 2 (ClinVar).

How common is EXT2 p.Phe400Leu (c.1200C>A) in the general population?

EXT2 p.Phe400Leu (c.1200C>A) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

What do computational predictors say about EXT2 p.Phe400Leu (c.1200C>A)?

AlphaMissense predicts likely pathogenic (score 0.9184) — an in-silico prediction, not a clinical call.

EXT2 p.Phe400Leu

c.1200C>A · rs773613001 · VCV849654

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.9184	likely pathogenic
REVEL	0.76	pathogenic-leaning
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.086, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	23.1	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 0.0535% East Asian · 24/44,870 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00155% 25/1,614,144 alleles · ultra-rare exomes 20/1,461,882 · genomes 5/152,262 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,870
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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.Phe400Leu
Coding: c.1200C>A
MANE Select: NM_207122
dbSNP: rs773613001
Type: single nucleotide variant
Location: chr11:44171637 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 400: an α-helix

Full EXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: exostoses, multiple, type 2

Similar variants

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
EXT2 c.626+1G>A Pathogenic ★★ same condition
EXT2 c.626+1G>C Pathogenic ★★ same condition
EXT2 c.626+1G>T Pathogenic/Likely 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-phe400leu (accessed [today's date]).

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