Is PYROXD1 p.Lys264Arg (c.791A>G) pathogenic?

PYROXD1 p.Lys264Arg (c.791A>G) is classified Uncertain significance in PYROXD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0808); Ultra-rare (popmax 0.0144%, amr); Associated with Inborn genetic diseases.

What condition is associated with PYROXD1 p.Lys264Arg (c.791A>G)?

PYROXD1 p.Lys264Arg (c.791A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PYROXD1 p.Lys264Arg (c.791A>G) in the general population?

PYROXD1 p.Lys264Arg (c.791A>G) is ultra-rare (popmax 0.0144%, amr) (gnomAD).

What do computational predictors say about PYROXD1 p.Lys264Arg (c.791A>G)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

PYROXD1 p.Lys264Arg

c.791A>G · rs758238573 · VCV1418407

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 19 kb · p 2.6e-08 · regional, not allelic
Overall
CADD	21.3	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 0.0144% Admixed American · 8/55,368 alleles

Filtering AF 0.00709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00517%

Overall 0.000828% 13/1,569,976 alleles · ultra-rare exomes 12/1,417,764 · genomes 1/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0144%	6,921
South Asian	0.0024%	41,734
East Asian	0.00228%	43,848
European (non-Finnish)	0.000173%	577,634

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: PYROXD1
Protein: p.Lys264Arg
Coding: c.791A>G
MANE Select: NM_024854
dbSNP: rs758238573
Type: single nucleotide variant
Location: chr12:21461065 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.64 · 2 PDB
Residue 264: a β-strand

Full PYROXD1 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

PYROXD1 p.Ala393Val Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asn52Asp Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp352Gly Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp466Asn Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp64Asn Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp64His Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Glu241Asp Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Gly232Arg 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/pyroxd1-p-lys264arg (accessed [today's date]).

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