Is EXT1 p.Phe659Leu (c.1975T>C) pathogenic?

EXT1 p.Phe659Leu (c.1975T>C) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.976); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXT1 p.Phe659Leu (c.1975T>C)?

EXT1 p.Phe659Leu (c.1975T>C) is associated with Inborn genetic diseases (ClinVar).

How common is EXT1 p.Phe659Leu (c.1975T>C) in the general population?

EXT1 p.Phe659Leu (c.1975T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EXT1 p.Phe659Leu (c.1975T>C)?

AlphaMissense predicts likely pathogenic (score 0.976) — an in-silico prediction, not a clinical call.

EXT1 p.Phe659Leu

c.1975T>C · VCV4618954

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.976	likely pathogenic
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -12.17	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 13 kb · p 1.9e-10 · regional, not allelic
Overall
CADD	25.2	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 8.47e-05% European (non-Finnish) · 1/1,179,998 alleles

Overall 6.2e-05% 1/1,614,154 alleles · very rare exomes 1/1,461,848 · genomes 0/152,306 · 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: EXT1
Protein: p.Phe659Leu
Coding: c.1975T>C
MANE Select: NM_000127
Type: single nucleotide variant
Location: chr8:117804802 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB
Residue 659: an α-helix

Full EXT1 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

EXT1 p.Trp68Ter Pathogenic ★★ same condition
EXT1 p.Ala689Thr Uncertain significance ★★ ⚠ same condition
EXT1 p.Arg37Lys Uncertain significance ★★ ⚠ same condition
EXT1 p.Asn555Asp Uncertain significance ★★ ⚠ same condition
EXT1 p.Asp52Tyr Uncertain significance ★★ ⚠ same condition
EXT1 p.Asp615Asn Uncertain significance ★★ same condition
EXT1 p.Glu38Gly Uncertain significance ★★ ⚠ same condition
EXT1 p.Glu413Asp 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/ext1-p-phe659leu (accessed [today's date]).

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