Is PTDSS2 p.Pro164Ser (c.490C>T) pathogenic?

PTDSS2 p.Pro164Ser (c.490C>T) is classified Uncertain significance in PTDSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely benign (0.1308); Ultra-rare (popmax 0.0154%, sas).

How common is PTDSS2 p.Pro164Ser (c.490C>T) in the general population?

PTDSS2 p.Pro164Ser (c.490C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about PTDSS2 p.Pro164Ser (c.490C>T)?

AlphaMissense predicts likely benign (score 0.1308) — an in-silico prediction, not a clinical call.

PTDSS2 p.Pro164Ser

c.490C>T · VCV3940082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1308 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1308	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -10.33	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 38 kb · p 2e-07 · regional, not allelic
Overall
CADD	22.2	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 0.0154% South Asian · 14/91,016 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00105% 17/1,613,348 alleles · ultra-rare exomes 14/1,460,994 · genomes 3/152,354 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,501
East Asian	0.00446%	22,445
European (non-Finnish)	8.48e-05%	1,179,864

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.Pro164Ser
Coding: c.490C>T
MANE Select: NM_030783
Type: single nucleotide variant
Location: chr11:486993 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.93 · 1 PDB

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-pro164ser (accessed [today's date]).

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