Is EXTL3 p.Arg84His (c.251G>A) pathogenic?

EXTL3 p.Arg84His (c.251G>A) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-30). AlphaMissense: likely benign (0.2258); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with EXTL3 p.Arg84His (c.251G>A)?

EXTL3 p.Arg84His (c.251G>A) is associated with Inborn genetic diseases (ClinVar).

How common is EXTL3 p.Arg84His (c.251G>A) in the general population?

EXTL3 p.Arg84His (c.251G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about EXTL3 p.Arg84His (c.251G>A)?

AlphaMissense predicts likely benign (score 0.2258) — an in-silico prediction, not a clinical call.

EXTL3 p.Arg84His

c.251G>A · rs1367166867 · VCV2262553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2258	likely benign
REVEL	0.652	pathogenic-leaning
SaProt	LLR -7.07	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,803 bp · p 0.01 · regional, not allelic
Overall
CADD	31.0	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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000682% 11/1,614,054 alleles · very rare exomes 9/1,461,830 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000678%	147,504

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.Arg84His
Coding: c.251G>A
MANE Select: NM_001440
dbSNP: rs1367166867
Type: single nucleotide variant
Location: chr8:28716310 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB
Residue 84: the 'required for interaction with reg3a' region

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.Arg84Cys Uncertain significance ★ ⚠ same residue
EXTL3 p.Arg84= Likely benign ★ same residue
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

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-arg84his (accessed [today's date]).

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