Is THOP1 p.Pro595Ser (c.1783C>T) pathogenic?

THOP1 p.Pro595Ser (c.1783C>T) is classified Uncertain significance in THOP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-14). AlphaMissense: ambiguous (0.4695); Very rare (popmax 0.00534%, afr).

How common is THOP1 p.Pro595Ser (c.1783C>T) in the general population?

THOP1 p.Pro595Ser (c.1783C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about THOP1 p.Pro595Ser (c.1783C>T)?

AlphaMissense predicts ambiguous (score 0.4695) — an in-silico prediction, not a clinical call.

THOP1 p.Pro595Ser

c.1783C>T · rs1308491805 · VCV2560306

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4695	ambiguous
REVEL	0.18	moderately benign-leaning
SaProt	LLR -11.37	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.75, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 28 kb · p 2.2e-05 · regional, not allelic
Overall
CADD	24.1	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 0.00534% African / African-American · 4/74,936 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,612,802 alleles · very rare exomes 2/1,460,584 · genomes 2/152,218 · 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: THOP1
Protein: p.Pro595Ser
Coding: c.1783C>T
MANE Select: NM_003249
dbSNP: rs1308491805
Type: single nucleotide variant
Location: chr19:2811609 (GRCh38)
Gene constraint: LOEUF 0.876 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.11 · 2 PDB
Residue 595: an α-helix

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-pro595ser (accessed [today's date]).

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