Is EXT1 p.Pro51Leu (c.152C>T) pathogenic?

EXT1 p.Pro51Leu (c.152C>T) is classified Uncertain significance in EXT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.0882); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with EXT1 p.Pro51Leu (c.152C>T)?

EXT1 p.Pro51Leu (c.152C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXT1 p.Pro51Leu (c.152C>T) in the general population?

EXT1 p.Pro51Leu (c.152C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about EXT1 p.Pro51Leu (c.152C>T)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

EXT1 p.Pro51Leu

c.152C>T · VCV4020578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 5.1, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 371 bp · p 0.2 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00134% African / African-American · 1/74,896 alleles

Overall 6.2e-05% 1/1,613,924 alleles · very rare exomes 0/1,461,806 · genomes 1/152,118 · 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.Pro51Leu
Coding: c.152C>T
MANE Select: NM_000127
Type: single nucleotide variant
Location: chr8:118110895 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 6 PDB

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.Pro51= Likely benign ★ same residue
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

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-pro51leu (accessed [today's date]).

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