Is EXTL3 p.His751Arg (c.2252A>G) pathogenic?

EXTL3 p.His751Arg (c.2252A>G) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-21). AlphaMissense: likely pathogenic (0.9549); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with EXTL3 p.His751Arg (c.2252A>G)?

EXTL3 p.His751Arg (c.2252A>G) is associated with Inborn genetic diseases (ClinVar).

How common is EXTL3 p.His751Arg (c.2252A>G) in the general population?

EXTL3 p.His751Arg (c.2252A>G) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about EXTL3 p.His751Arg (c.2252A>G)?

AlphaMissense predicts likely pathogenic (score 0.9549) — an in-silico prediction, not a clinical call.

EXTL3 p.His751Arg

c.2252A>G · VCV3511114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9549 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9549	likely pathogenic
REVEL	0.693	pathogenic-leaning
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 33 kb · p 2.6e-14 · regional, not allelic
Overall
CADD	26.3	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 0.0134% East Asian · 6/44,892 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00149% 24/1,614,264 alleles · ultra-rare exomes 24/1,461,886 · genomes 0/152,378 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,482
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.00136%	73,753
African / African-American	0.00133%	75,068

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.His751Arg
Coding: c.2252A>G
MANE Select: NM_001440
Type: single nucleotide variant
Location: chr8:28731326 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB
Residue 751: an α-helix

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-his751arg (accessed [today's date]).

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