Is EXTL3 p.Val298Leu (c.892G>T) pathogenic?

EXTL3 p.Val298Leu (c.892G>T) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.2098); Very rare (popmax 0.00833%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXTL3 p.Val298Leu (c.892G>T)?

EXTL3 p.Val298Leu (c.892G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXTL3 p.Val298Leu (c.892G>T) in the general population?

EXTL3 p.Val298Leu (c.892G>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about EXTL3 p.Val298Leu (c.892G>T)?

AlphaMissense predicts likely benign (score 0.2098) — an in-silico prediction, not a clinical call.

EXTL3 p.Val298Leu

c.892G>T · VCV4020596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2098	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,803 bp · p 0.01 · regional, not allelic
Overall
CADD	19.89	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 0.00833% Admixed American · 5/60,004 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000434% 7/1,614,102 alleles · very rare exomes 2/1,461,890 · genomes 5/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,001
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,922

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.Val298Leu
Coding: c.892G>T
MANE Select: NM_001440
Type: single nucleotide variant
Location: chr8:28716951 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB
Residue 298: a β-strand

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.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
EXTL3 p.Ala820Thr Uncertain significance ★★ same condition
EXTL3 p.Arg175Trp 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-val298leu (accessed [today's date]).

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