Is PYROXD2 p.Lys309Arg (c.926A>G) pathogenic?

PYROXD2 p.Lys309Arg (c.926A>G) is classified Uncertain significance in PYROXD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0946); Ultra-rare (popmax 0.0682%, sas).

How common is PYROXD2 p.Lys309Arg (c.926A>G) in the general population?

PYROXD2 p.Lys309Arg (c.926A>G) is ultra-rare (popmax 0.0682%, sas) (gnomAD).

What do computational predictors say about PYROXD2 p.Lys309Arg (c.926A>G)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

PYROXD2 p.Lys309Arg

c.926A>G · VCV4148768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0682%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -5.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.48	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 31 kb · p 0.89 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0682% South Asian · 62/90,924 alleles

Filtering AF 0.0545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0496%

Overall 0.00391% 63/1,612,872 alleles · ultra-rare exomes 56/1,460,590 · genomes 7/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0682%	1,467
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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: PYROXD2
Protein: p.Lys309Arg
Coding: c.926A>G
MANE Select: NM_032709
Type: single nucleotide variant
Location: chr10:98392943 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.56

Full PYROXD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PYROXD2 c.1062+2T>G Uncertain significance ★ same type
PYROXD2 p.Ala172Asp Uncertain significance ★ ⚠ same type
PYROXD2 p.Ala293Val Uncertain significance ★ ⚠ same type
PYROXD2 p.Ala303Ser Uncertain significance ★ ⚠ same type
PYROXD2 p.Ala312Val Uncertain significance ★ ⚠ same type
PYROXD2 p.Ala389Val Uncertain significance ★ ⚠ same type
PYROXD2 p.Ala390Val Uncertain significance ★ ⚠ same type
PYROXD2 p.Ala524Thr 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/pyroxd2-p-lys309arg (accessed [today's date]).

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