Is PYROXD1 p.Ala427Pro (c.1279G>C) pathogenic?

PYROXD1 p.Ala427Pro (c.1279G>C) is classified Uncertain significance in PYROXD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-12). AlphaMissense: likely pathogenic (0.9111); Very rare (popmax 0.00401%, afr).

How common is PYROXD1 p.Ala427Pro (c.1279G>C) in the general population?

PYROXD1 p.Ala427Pro (c.1279G>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PYROXD1 p.Ala427Pro (c.1279G>C)?

AlphaMissense predicts likely pathogenic (score 0.9111) — an in-silico prediction, not a clinical call.

PYROXD1 p.Ala427Pro

c.1279G>C · rs1193283089 · VCV1394732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9111	likely pathogenic
REVEL	0.277	benign-leaning
SaProt	LLR -14.34	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP 1.8, phastCons 0.24
Regional constraint	o/e 0.74	unconstrained · MANE · 19 kb · p 2.6e-08 · regional, not allelic
Overall
CADD	24.7	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 0.00401% African / African-American · 3/74,838 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,612,420 alleles · very rare exomes 1/1,460,346 · genomes 2/152,074 · joint denominator

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.Ala427Pro
Coding: c.1279G>C
MANE Select: NM_024854
dbSNP: rs1193283089
Type: single nucleotide variant
Location: chr12:21468530 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.64 · 2 PDB

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

Similar variants

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
PYROXD1 p.Arg76Cys Uncertain significance ★★ ⚠ same type
PYROXD1 p.Asn52Asp 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-ala427pro (accessed [today's date]).

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