Is PYROXD1 p.Ser35Leu (c.104C>T) pathogenic?

PYROXD1 p.Ser35Leu (c.104C>T) is classified Uncertain significance in PYROXD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-30). AlphaMissense: likely benign (0.0791); Ultra-rare (popmax 0.0315%, amr); Associated with Inborn genetic diseases.

What condition is associated with PYROXD1 p.Ser35Leu (c.104C>T)?

PYROXD1 p.Ser35Leu (c.104C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PYROXD1 p.Ser35Leu (c.104C>T) in the general population?

PYROXD1 p.Ser35Leu (c.104C>T) is ultra-rare (popmax 0.0315%, amr) (gnomAD).

What do computational predictors say about PYROXD1 p.Ser35Leu (c.104C>T)?

AlphaMissense predicts likely benign (score 0.0791) — an in-silico prediction, not a clinical call.

PYROXD1 p.Ser35Leu

c.104C>T · rs151083272 · VCV1435084

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0791 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0315%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0791	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -8.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
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	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0315% Admixed American · 18/57,080 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00978% 156/1,594,632 alleles · ultra-rare exomes 114/1,442,386 · genomes 42/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0315%	3,171
African / African-American	0.0311%	3,218
Remaining individualsnot grpmax-eligible	0.0259%	3,857
European (non-Finnish)	0.00812%	12,320
South Asian	0.00459%	21,773

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.Ser35Leu
Coding: c.104C>T
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.Ser35Trp 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-ser35leu (accessed [today's date]).

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