Is EXTL3 p.Pro714Arg (c.2141C>G) pathogenic?

EXTL3 p.Pro714Arg (c.2141C>G) is classified Uncertain significance in EXTL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-19). AlphaMissense: ambiguous (0.3669); Very rare (popmax 0.00329%, sas).

How common is EXTL3 p.Pro714Arg (c.2141C>G) in the general population?

EXTL3 p.Pro714Arg (c.2141C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about EXTL3 p.Pro714Arg (c.2141C>G)?

AlphaMissense predicts ambiguous (score 0.3669) — an in-silico prediction, not a clinical call.

EXTL3 p.Pro714Arg

c.2141C>G · rs1801208888 · VCV1438795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3669	ambiguous
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -8.30	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 33 kb · p 2.6e-14 · regional, not allelic
Overall
CADD	27.8	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 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,613,940 alleles · very rare exomes 4/1,461,688 · genomes 0/152,252 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
European (non-Finnish)	8.48e-05%	1,179,924

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.Pro714Arg
Coding: c.2141C>G
MANE Select: NM_001440
dbSNP: rs1801208888
Type: single nucleotide variant
Location: chr8:28718200 (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

Similar variants

EXTL3 p.Pro318Leu Pathogenic/Likely pathogenic ★★ ⚠ same type
EXTL3 p.Ala373Thr Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala385Val Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala481Val Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala482Thr Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala507Ser Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala560Ser Uncertain significance ★★ ⚠ same type
EXTL3 p.Ala585Thr Uncertain significance ★★ ⚠ same type

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-pro714arg (accessed [today's date]).

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