Is PYROXD1 p.Pro491Leu (c.1472C>T) pathogenic?

PYROXD1 p.Pro491Leu (c.1472C>T) is classified Uncertain significance in PYROXD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-23). AlphaMissense: ambiguous (0.3437); Very rare (popmax 0.00447%, eas).

How common is PYROXD1 p.Pro491Leu (c.1472C>T) in the general population?

PYROXD1 p.Pro491Leu (c.1472C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about PYROXD1 p.Pro491Leu (c.1472C>T)?

AlphaMissense predicts ambiguous (score 0.3437) — an in-silico prediction, not a clinical call.

PYROXD1 p.Pro491Leu

c.1472C>T · VCV4975380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3437 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Computational evidence

Protein change
AlphaMissense	0.3437	ambiguous
REVEL	0.457	indeterminate
SaProt	LLR -12.43	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 19 kb · p 2.6e-08 · regional, not allelic
Overall
CADD	27.5	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 0.00447% East Asian · 2/44,716 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,608,004 alleles · very rare exomes 0/1,456,156 · genomes 2/151,848 · 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.Pro491Leu
Coding: c.1472C>T
MANE Select: NM_024854
Type: single nucleotide variant
Location: chr12:21468723 (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-pro491leu (accessed [today's date]).

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