Is EXTL3 p.Pro731Arg (c.2192C>G) pathogenic?

EXTL3 p.Pro731Arg (c.2192C>G) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.9878); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXTL3 p.Pro731Arg (c.2192C>G)?

EXTL3 p.Pro731Arg (c.2192C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EXTL3 p.Pro731Arg (c.2192C>G) in the general population?

EXTL3 p.Pro731Arg (c.2192C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EXTL3 p.Pro731Arg (c.2192C>G)?

AlphaMissense predicts likely pathogenic (score 0.9878) — an in-silico prediction, not a clinical call.

EXTL3 p.Pro731Arg

c.2192C>G · VCV4252156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9878	likely pathogenic
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -13.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 0.92, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 33 kb · p 2.6e-14 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000339% European (non-Finnish) · 4/1,179,954 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,942 alleles · very rare exomes 3/1,461,816 · genomes 1/152,126 · 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.Pro731Arg
Coding: c.2192C>G
MANE Select: NM_001440
Type: single nucleotide variant
Location: chr8:28731266 (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

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-pro731arg (accessed [today's date]).

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