Is THUMPD1 p.Pro85Ser (c.253C>T) pathogenic?

THUMPD1 p.Pro85Ser (c.253C>T) is classified Uncertain significance in THUMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely benign (0.0675); Ultra-rare (popmax 0.0999%, sas); Associated with Inborn genetic diseases.

What condition is associated with THUMPD1 p.Pro85Ser (c.253C>T)?

THUMPD1 p.Pro85Ser (c.253C>T) is associated with Inborn genetic diseases (ClinVar).

How common is THUMPD1 p.Pro85Ser (c.253C>T) in the general population?

THUMPD1 p.Pro85Ser (c.253C>T) is ultra-rare (popmax 0.0999%, sas) (gnomAD).

What do computational predictors say about THUMPD1 p.Pro85Ser (c.253C>T)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

THUMPD1 p.Pro85Ser

c.253C>T · rs142407123 · VCV2358846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0999%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -4.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.1	GERP -1.1, phastCons 0.068
Regional constraint	o/e 1.04	unconstrained · MANE · 4,856 bp · p 0.38 · regional, not allelic
Overall
CADD	9.551	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 0.0999% South Asian · 91/91,084 alleles

Filtering AF 0.0833% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0771%

Overall 0.0655% 1,057/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0999%	1,001
European (non-Finnish)	0.0755%	1,324
Admixed American	0.0483%	2,069
Remaining individualsnot grpmax-eligible	0.0432%	2,315
Finnishnot grpmax-eligible	0.0172%	5,818
African / African-American	0.0107%	9,378

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: THUMPD1
Protein: p.Pro85Ser
Coding: c.253C>T
MANE Select: NM_017736
dbSNP: rs142407123
Type: single nucleotide variant
Location: chr16:20739050 (GRCh38)

Full THUMPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/thumpd1-p-pro85ser (accessed [today's date]).

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