Is EXT2 p.Lys436Arg (c.1307A>G) pathogenic?

EXT2 p.Lys436Arg (c.1307A>G) is classified Uncertain significance in EXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-05). AlphaMissense: likely benign (0.0742); Very rare (popmax 0.00017%, nfe).

How common is EXT2 p.Lys436Arg (c.1307A>G) in the general population?

EXT2 p.Lys436Arg (c.1307A>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about EXT2 p.Lys436Arg (c.1307A>G)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

EXT2 p.Lys436Arg

c.1307A>G · VCV4885663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -5.94	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 9.4	GERP 0.81, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 99 kb · p 0.085 · regional, not allelic
Overall
CADD	22.0	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 0.00017% European (non-Finnish) · 2/1,179,924 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,968 alleles · very rare exomes 2/1,461,708 · genomes 0/152,260 · 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.Lys436Arg
Coding: c.1307A>G
MANE Select: NM_207122
Type: single nucleotide variant
Location: chr11:44197830 (GRCh38)
Gene constraint: LOEUF 0.775 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.59 · 6 PDB
Residue 436: an α-helix

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

Similar variants

EXT2 p.Lys436Asn Uncertain significance ★ ⚠ same residue
EXT2 p.Lys436= Likely benign ★ 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-lys436arg (accessed [today's date]).

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