Is TTPA p.Pro89Ser (c.265C>T) pathogenic?

TTPA p.Pro89Ser (c.265C>T) is classified Uncertain significance in TTPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-16). AlphaMissense: likely pathogenic (0.797); Ultra-rare (popmax 0.016%, afr).

How common is TTPA p.Pro89Ser (c.265C>T) in the general population?

TTPA p.Pro89Ser (c.265C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about TTPA p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely pathogenic (score 0.797) — an in-silico prediction, not a clinical call.

TTPA p.Pro89Ser

c.265C>T · rs374272548 · VCV1372046

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.797	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 25 kb · p 0.39 · regional, not allelic
Overall
CADD	26.6	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 0.016% African / African-American · 12/74,830 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000868% 14/1,613,350 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,236
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	8.48e-05%	1,179,619

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: TTPA
Protein: p.Pro89Ser
Coding: c.265C>T
MANE Select: NM_000370
dbSNP: rs374272548
Type: single nucleotide variant
Location: chr8:63073028 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 6 PDB
Residue 89: the cral-trio domain; an α-helix

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

Similar variants

TTPA p.Pro89fs Pathogenic ★ same residue
TTPA c.205-1G>C Pathogenic ★★ same type
TTPA c.205-2A>G Pathogenic/Likely pathogenic ★★ same type
TTPA c.553-1G>T Pathogenic ★★ same type
TTPA c.663+1G>A Pathogenic/Likely pathogenic ★★ same type
TTPA p.Ala120Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
TTPA p.Ala58Asp Likely pathogenic ★★ same type
TTPA p.Arg134Ter Pathogenic ★★ 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/ttpa-p-pro89ser (accessed [today's date]).

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