Is EXT2 p.Leu177= (c.531C>G) pathogenic?

EXT2 p.Leu177= (c.531C>G) is classified Likely benign in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). Ultra-rare (popmax 0.0496%, mid).

How common is EXT2 p.Leu177= (c.531C>G) in the general population?

EXT2 p.Leu177= (c.531C>G) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

EXT2 p.Leu177=

c.531C>G · VCV4911282

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.089	GERP -0.66, phastCons 0.92
Overall
CADD	6.762	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0496% Middle Eastern · 3/6,052 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.000186% 3/1,611,814 alleles · ultra-rare exomes 3/1,459,490 · genomes 0/152,324 · 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.Leu177=
Coding: c.531C>G
MANE Select: NM_207122
Type: single nucleotide variant
Location: chr11:44108243 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB

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

Similar variants

EXT2 p.Leu177_Ser178insTer Likely pathogenic ★ same residue
EXT2 p.Leu177Ile Uncertain significance ★ same residue
EXT2 c.1079+1G>A Pathogenic ★★ same type
EXT2 c.1079+1G>T Pathogenic ★★ same type
EXT2 c.1173+1G>A Pathogenic ★★ same type
EXT2 c.1662+1G>C Likely pathogenic ★★ same type
EXT2 c.536+1G>A Pathogenic ★★ same type
EXT2 c.626+1G>A Pathogenic ★★ same type

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-leu177 (accessed [today's date]).

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