Is EXTL3 p.Ala652Ser (c.1954G>T) pathogenic?

EXTL3 p.Ala652Ser (c.1954G>T) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-23). AlphaMissense: likely benign (0.0854); Very rare (popmax 0.000169%, nfe).

How common is EXTL3 p.Ala652Ser (c.1954G>T) in the general population?

EXTL3 p.Ala652Ser (c.1954G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about EXTL3 p.Ala652Ser (c.1954G>T)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

EXTL3 p.Ala652Ser

c.1954G>T · rs1278924019 · VCV1485407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.431	indeterminate
SaProt	LLR -3.87	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 33 kb · p 2.6e-14 · regional, not allelic
Overall
CADD	24.4	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 0.000169% European (non-Finnish) · 2/1,180,024 alleles

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

Overall 0.000124% 2/1,613,952 alleles · very rare exomes 1/1,461,894 · genomes 1/152,058 · 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.Ala652Ser
Coding: c.1954G>T
MANE Select: NM_001440
dbSNP: rs1278924019
Type: single nucleotide variant
Location: chr8:28718013 (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.Ala652= 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-ala652ser (accessed [today's date]).

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