Is EXTL3 p.Val69Ala (c.206T>C) pathogenic?

EXTL3 p.Val69Ala (c.206T>C) is classified Conflicting classifications of pathogenicity in EXTL3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.0516); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with EXTL3 p.Val69Ala (c.206T>C)?

EXTL3 p.Val69Ala (c.206T>C) is associated with Inborn genetic diseases (ClinVar).

How common is EXTL3 p.Val69Ala (c.206T>C) in the general population?

EXTL3 p.Val69Ala (c.206T>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about EXTL3 p.Val69Ala (c.206T>C)?

AlphaMissense predicts likely benign (score 0.0516) — an in-silico prediction, not a clinical call.

EXTL3 p.Val69Ala

c.206T>C · rs746203687 · VCV2186103

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0516 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0516	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.78, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,803 bp · p 0.01 · regional, not allelic
Overall
CADD	17.47	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,878 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,613,906 alleles · very rare exomes 2/1,461,882 · genomes 2/152,024 · 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: EXTL3
Protein: p.Val69Ala
Coding: c.206T>C
MANE Select: NM_001440
dbSNP: rs746203687
Type: single nucleotide variant
Location: chr8:28716265 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB
Residue 69: the 'required for interaction with reg3a' region

Full EXTL3 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

EXTL3 p.Val69Leu Uncertain significance ★ ⚠ same residue
EXTL3 p.Val69Met Uncertain significance ★ ⚠ same residue
EXTL3 p.Ala373Thr Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala385Val Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala481Val Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala482Thr Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala560Ser Uncertain significance ★★ ⚠ same condition
EXTL3 p.Ala585Thr 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/extl3-p-val69ala (accessed [today's date]).

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