Is PYROXD1 p.Val319Asp (c.956T>A) pathogenic?

PYROXD1 p.Val319Asp (c.956T>A) is classified Uncertain significance in PYROXD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-14). AlphaMissense: likely pathogenic (0.9891); Very rare (popmax 0.00017%, nfe).

How common is PYROXD1 p.Val319Asp (c.956T>A) in the general population?

PYROXD1 p.Val319Asp (c.956T>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PYROXD1 p.Val319Asp (c.956T>A)?

AlphaMissense predicts likely pathogenic (score 0.9891) — an in-silico prediction, not a clinical call.

PYROXD1 p.Val319Asp

c.956T>A · rs911652877 · VCV1512635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9891	likely pathogenic · top 2% in PYROXD1
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -14.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 19 kb · p 2.6e-08 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,178,720 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,108 alleles · very rare exomes 2/1,460,028 · genomes 0/152,080 · 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.Val319Asp
Coding: c.956T>A
MANE Select: NM_024854
dbSNP: rs911652877
Type: single nucleotide variant
Location: chr12:21462083 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.64 · 2 PDB
Residue 319: a β-strand

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

Similar variants

PYROXD1 p.Val319Ile Uncertain significance ★ ⚠ 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
PYROXD1 p.Arg76Cys 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-val319asp (accessed [today's date]).

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