Is PYROXD1 p.Arg76His (c.227G>A) pathogenic?

PYROXD1 p.Arg76His (c.227G>A) is classified Uncertain significance in PYROXD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.0799); Very rare (popmax 0.00935%, afr).

How common is PYROXD1 p.Arg76His (c.227G>A) in the general population?

PYROXD1 p.Arg76His (c.227G>A) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about PYROXD1 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.0799) — an in-silico prediction, not a clinical call.

PYROXD1 p.Arg76His

c.227G>A · VCV4752132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0799	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -9.41	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 5.1	GERP 1.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 12 kb · p 0.65 · regional, not allelic
Overall
CADD	23.6	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 0.00935% African / African-American · 7/74,868 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000808% 13/1,609,286 alleles · very rare exomes 13/1,457,004 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,695
Remaining individualsnot grpmax-eligible	0.00321%	31,155
South Asian	0.00112%	89,504
European (non-Finnish)	0.000255%	392,862

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.Arg76His
Coding: c.227G>A
MANE Select: NM_024854
Type: single nucleotide variant
Location: chr12:21445408 (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.Arg76Cys 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-arg76his (accessed [today's date]).

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