Is THOP1 p.Ser91Phe (c.272C>T) pathogenic?

THOP1 p.Ser91Phe (c.272C>T) is classified Uncertain significance in THOP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely benign (0.2797); Very rare (popmax 0.00169%, nfe).

How common is THOP1 p.Ser91Phe (c.272C>T) in the general population?

THOP1 p.Ser91Phe (c.272C>T) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about THOP1 p.Ser91Phe (c.272C>T)?

AlphaMissense predicts likely benign (score 0.2797) — an in-silico prediction, not a clinical call.

THOP1 p.Ser91Phe

c.272C>T · VCV3456237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2797	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.3	GERP -5.7
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 2.2e-05 · regional, not allelic
Overall
CADD	9.573	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 0.00169% European (non-Finnish) · 20/1,179,942 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,613,990 alleles · very rare exomes 21/1,461,722 · genomes 0/152,268 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	58,997
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: THOP1
Protein: p.Ser91Phe
Coding: c.272C>T
MANE Select: NM_003249
Type: single nucleotide variant
Location: chr19:2794806 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.11 · 2 PDB

Full THOP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

THOP1 p.Ala139Val Uncertain significance ★ ⚠ same type
THOP1 p.Ala14Thr Uncertain significance ★ ⚠ same type
THOP1 p.Ala292Val Uncertain significance ★ ⚠ same type
THOP1 p.Ala299Val Uncertain significance ★ ⚠ same type
THOP1 p.Ala319Val Uncertain significance ★ ⚠ same type
THOP1 p.Ala387Thr Uncertain significance ★ ⚠ same type
THOP1 p.Ala446Val Uncertain significance ★ ⚠ same type
THOP1 p.Ala503Val 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/thop1-p-ser91phe (accessed [today's date]).

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