Is EXT2 p.Ser138Ala (c.412T>G) pathogenic?

EXT2 p.Ser138Ala (c.412T>G) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0592); Very rare (popmax 0.008%, afr); Associated with Inborn genetic diseases.

What condition is associated with EXT2 p.Ser138Ala (c.412T>G)?

EXT2 p.Ser138Ala (c.412T>G) is associated with Inborn genetic diseases (ClinVar).

How common is EXT2 p.Ser138Ala (c.412T>G) in the general population?

EXT2 p.Ser138Ala (c.412T>G) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about EXT2 p.Ser138Ala (c.412T>G)?

AlphaMissense predicts likely benign (score 0.0592) — an in-silico prediction, not a clinical call.

EXT2 p.Ser138Ala

c.412T>G · VCV4252123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0592	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -6.21	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 1	GERP -1.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	13.28	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 0.008% African / African-American · 6/75,020 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000434% 7/1,614,154 alleles · very rare exomes 3/1,461,886 · genomes 4/152,268 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,503
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ser138Ala
Coding: c.412T>G
MANE Select: NM_207122
Type: single nucleotide variant
Location: chr11:44108124 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 138: an α-helix

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.Ser138Ter Pathogenic/Likely pathogenic ★★ 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-ser138ala (accessed [today's date]).

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