Is PTDSS2 p.Pro12Arg (c.35C>G) pathogenic?

PTDSS2 p.Pro12Arg (c.35C>G) is classified Uncertain significance in PTDSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0646); Very rare (popmax 8.09e-05%).

How common is PTDSS2 p.Pro12Arg (c.35C>G) in the general population?

PTDSS2 p.Pro12Arg (c.35C>G) is very rare (popmax 8.09e-05%) (gnomAD).

What do computational predictors say about PTDSS2 p.Pro12Arg (c.35C>G)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

PTDSS2 p.Pro12Arg

c.35C>G · VCV4146990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.09e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.42	GERP -2.1, phastCons 0.001
Regional constraint	o/e 0.72	unconstrained · MANE · 38 kb · p 2e-07 · regional, not allelic
Overall
CADD	11.7	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 8.09e-05%

Overall 8.09e-05% 1/1,235,776 alleles · very rare exomes 1/1,083,572 · genomes 0/152,204 · 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: PTDSS2
Protein: p.Pro12Arg
Coding: c.35C>G
MANE Select: NM_030783
Type: single nucleotide variant
Location: chr11:450490 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.93 · 1 PDB
Residue 12: the 'disordered' region

Full PTDSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTDSS2 p.Gln454Arg Uncertain significance ★★ ⚠ same type
PTDSS2 p.Ala199Thr Uncertain significance ★ same type
PTDSS2 p.Ala20Thr Uncertain significance ★ ⚠ same type
PTDSS2 p.Ala20Val Uncertain significance ★ ⚠ same type
PTDSS2 p.Ala37Thr Uncertain significance ★ ⚠ same type
PTDSS2 p.Arg313Ser Uncertain significance ★ ⚠ same type
PTDSS2 p.Arg430His Uncertain significance ★ ⚠ same type
PTDSS2 p.Arg434Trp 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/ptdss2-p-pro12arg (accessed [today's date]).

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