Is PYROXD1 p.Ser35Trp (c.104C>G) pathogenic?

PYROXD1 p.Ser35Trp (c.104C>G) is classified Uncertain significance in PYROXD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-13). AlphaMissense: likely benign (0.1689); Ultra-rare (popmax 0.0325%, afr); Associated with Inborn genetic diseases.

What condition is associated with PYROXD1 p.Ser35Trp (c.104C>G)?

PYROXD1 p.Ser35Trp (c.104C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PYROXD1 p.Ser35Trp (c.104C>G) in the general population?

PYROXD1 p.Ser35Trp (c.104C>G) is ultra-rare (popmax 0.0325%, afr) (gnomAD).

What do computational predictors say about PYROXD1 p.Ser35Trp (c.104C>G)?

AlphaMissense predicts likely benign (score 0.1689) — an in-silico prediction, not a clinical call.

PYROXD1 p.Ser35Trp

c.104C>G · rs151083272 · VCV2161769

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1689 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1689	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -12.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.83	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 12 kb · p 0.65 · regional, not allelic
Overall
CADD	25.4	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 0.0325% African / African-American · 24/73,884 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.00157% 25/1,594,516 alleles · ultra-rare exomes 10/1,442,388 · genomes 15/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0325%	3,078
South Asian	0.00115%	87,098

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.Ser35Trp
Coding: c.104C>G
MANE Select: NM_024854
dbSNP: rs151083272
Type: single nucleotide variant
Location: chr12:21440387 (GRCh38)
Gene constraint: LOEUF 1.107 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.64 · 2 PDB
Residue 35: a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PYROXD1 p.Ser35Leu Uncertain significance ★★ ⚠ same residue
PYROXD1 p.Ser35= Likely benign ★ same residue
PYROXD1 p.Ala393Val Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asn52Asp Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp352Gly Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp466Asn Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp64Asn Uncertain significance ★★ ⚠ same condition
PYROXD1 p.Asp64His Uncertain significance ★★ ⚠ same condition

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-ser35trp (accessed [today's date]).

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