Is EXTL3 p.Arg759= (c.2277G>T) pathogenic?

EXTL3 p.Arg759= (c.2277G>T) is classified Conflicting classifications of pathogenicity in EXTL3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-05-24). Ultra-rare (popmax 0.0317%, amr); Associated with Inborn genetic diseases.

What condition is associated with EXTL3 p.Arg759= (c.2277G>T)?

EXTL3 p.Arg759= (c.2277G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXTL3 p.Arg759= (c.2277G>T) in the general population?

EXTL3 p.Arg759= (c.2277G>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

EXTL3 p.Arg759=

c.2277G>T · rs144474985 · VCV1439307

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.087	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.82, phastCons 1
Overall
CADD	17.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/59,992 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00929% 150/1,613,844 alleles · ultra-rare exomes 147/1,461,652 · genomes 3/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,157
European (non-Finnish)	0.0107%	9,364
Remaining individualsnot grpmax-eligible	0.0064%	15,617
Finnishnot grpmax-eligible	0.00156%	64,036

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.Arg759=
Coding: c.2277G>T
MANE Select: NM_001440
dbSNP: rs144474985
Type: single nucleotide variant
Location: chr8:28737519 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 84.22 · 4 PDB
Residue 759: 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.Arg759Trp Uncertain significance ★ ⚠ 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
EXTL3 p.Ala820Thr 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-arg759 (accessed [today's date]).

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