Is PYROXD1 p.Pro34Leu (c.101C>T) pathogenic?

PYROXD1 p.Pro34Leu (c.101C>T) is classified Uncertain significance in PYROXD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: likely benign (0.1482); Very rare (popmax 0.00291%, nfe).

How common is PYROXD1 p.Pro34Leu (c.101C>T) in the general population?

PYROXD1 p.Pro34Leu (c.101C>T) is very rare (popmax 0.00291%, nfe) (gnomAD).

What do computational predictors say about PYROXD1 p.Pro34Leu (c.101C>T)?

AlphaMissense predicts likely benign (score 0.1482) — an in-silico prediction, not a clinical call.

PYROXD1 p.Pro34Leu

c.101C>T · rs1055730893 · VCV3003091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1482 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00291%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1482	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -11.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 12 kb · p 0.65 · regional, not allelic
Overall
CADD	28.3	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 0.00291% European (non-Finnish) · 34/1,169,360 alleles

Filtering AF 0.00209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.0022% 35/1,592,906 alleles · very rare exomes 33/1,440,826 · genomes 2/152,080 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00291%	34,393
African / African-American	0.00135%	73,832

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.Pro34Leu
Coding: c.101C>T
MANE Select: NM_024854
dbSNP: rs1055730893
Type: single nucleotide variant
Location: chr12:21440384 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.64 · 2 PDB
Residue 34: a β-strand

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

Similar variants

PYROXD1 p.Pro34= 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
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-pro34leu (accessed [today's date]).

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