Is TPSD1 p.Ser69Phe (c.206C>T) pathogenic?

TPSD1 p.Ser69Phe (c.206C>T) is classified Uncertain significance in TPSD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely pathogenic (0.9263); Very rare (popmax 0.0011%, sas).

How common is TPSD1 p.Ser69Phe (c.206C>T) in the general population?

TPSD1 p.Ser69Phe (c.206C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TPSD1 p.Ser69Phe (c.206C>T)?

AlphaMissense predicts likely pathogenic (score 0.9263) — an in-silico prediction, not a clinical call.

TPSD1 p.Ser69Phe

c.206C>T · rs755611201 · VCV3181664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9263	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -11.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP 1.8
Regional constraint	o/e 1.30	unconstrained · MANE · 2,092 bp · p 1.1e-07 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,032 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000744% 12/1,612,772 alleles · very rare exomes 11/1,460,548 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,432
South Asiangrpmax	0.0011%	91,032
European (non-Finnish)	0.000848%	117,969

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TPSD1
Protein: p.Ser69Phe
Coding: c.206C>T
MANE Select: NM_012217
dbSNP: rs755611201
Type: single nucleotide variant
Location: chr16:1256639 (GRCh38)
Gene constraint: LOEUF 1.747 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 85.89
Residue 69: the peptidase s1 domain

Full TPSD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TPSD1 p.Gly229Ser Benign ★★ ⚠ same type
TPSD1 p.Thr205= Benign ★★ same type
TPSD1 p.Ala15Val Uncertain significance ★ ⚠ same type
TPSD1 p.Ala197Thr Uncertain significance ★ ⚠ same type
TPSD1 p.Ala20Thr Uncertain significance ★ ⚠ same type
TPSD1 p.Ala5Gly Uncertain significance ★ ⚠ same type
TPSD1 p.Ala5Val Uncertain significance ★ ⚠ same type
TPSD1 p.Ala79Gly 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/tpsd1-p-ser69phe (accessed [today's date]).

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