Is PYROXD1 p.Arg76Cys (c.226C>T) pathogenic?

PYROXD1 p.Arg76Cys (c.226C>T) is classified Uncertain significance in PYROXD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: likely benign (0.0989); Ultra-rare (popmax 0.0268%, afr).

How common is PYROXD1 p.Arg76Cys (c.226C>T) in the general population?

PYROXD1 p.Arg76Cys (c.226C>T) is ultra-rare (popmax 0.0268%, afr) (gnomAD).

What do computational predictors say about PYROXD1 p.Arg76Cys (c.226C>T)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

PYROXD1 p.Arg76Cys

c.226C>T · rs149795907 · VCV1358320

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 1.9, phastCons 0.92
Regional constraint	o/e 1.04	unconstrained · MANE · 12 kb · p 0.65 · regional, not allelic
Overall
CADD	25.9	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 0.0268% African / African-American · 20/74,742 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0154% 248/1,609,126 alleles · ultra-rare exomes 218/1,456,944 · genomes 30/152,182 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0268%	3,737
Remaining individualsnot grpmax-eligible	0.0209%	4,790
Middle Eastern	0.017%	5,888
European (non-Finnish)	0.0164%	6,107
Admixed American	0.0152%	6,564
Finnishnot grpmax-eligible	0.0125%	7,988
East Asian	0.0067%	14,919
South Asian	0.00112%	89,502

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.Arg76Cys
Coding: c.226C>T
MANE Select: NM_024854
dbSNP: rs149795907
Type: single nucleotide variant
Location: chr12:21445407 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.64 · 2 PDB
Residue 76: an α-helix

Full PYROXD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PYROXD1 p.Arg76His Uncertain significance ★ ⚠ same residue
PYROXD1 p.Arg76= Likely benign ★ same residue
PYROXD1 c.285+1G>A Pathogenic/Likely pathogenic ★★ same type
PYROXD1 c.881-2A>T Likely pathogenic ★★ same type
PYROXD1 p.Asn155Ser Pathogenic ★★ same type
PYROXD1 p.Ala393Val Uncertain significance ★★ ⚠ same type
PYROXD1 p.Arg132Cys Uncertain significance ★★ ⚠ same type
PYROXD1 p.Arg455Gln 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/pyroxd1-p-arg76cys (accessed [today's date]).

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