Is EXTL3 p.Ala166Val (c.497C>T) pathogenic?

EXTL3 p.Ala166Val (c.497C>T) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.0684); Ultra-rare (popmax 0.0117%, amr).

How common is EXTL3 p.Ala166Val (c.497C>T) in the general population?

EXTL3 p.Ala166Val (c.497C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about EXTL3 p.Ala166Val (c.497C>T)?

AlphaMissense predicts likely benign (score 0.0684) — an in-silico prediction, not a clinical call.

EXTL3 p.Ala166Val

c.497C>T · rs753235953 · VCV1922807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0684 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0684	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -6.18	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 -0.092	GERP -0.6
Regional constraint	o/e 0.91	unconstrained · MANE · 1,803 bp · p 0.01 · regional, not allelic
Overall
CADD	2.255	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 0.0117% Admixed American · 7/60,030 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,614,156 alleles · ultra-rare exomes 7/1,461,840 · genomes 0/152,316 · 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.Ala166Val
Coding: c.497C>T
MANE Select: NM_001440
dbSNP: rs753235953
Type: single nucleotide variant
Location: chr8:28716556 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB

Full EXTL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXTL3 p.Ala166= Likely benign ★ same residue
EXTL3 p.Pro318Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
EXTL3 p.Ala373Thr Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala385Val Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala481Val Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala482Thr Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala507Ser Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala560Ser Uncertain significance ★★ ⚠ 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/extl3-p-ala166val (accessed [today's date]).

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