Is DTHD1 p.Ser734= (c.2202T>C) pathogenic?

DTHD1 p.Ser734= (c.2202T>C) is classified Benign/Likely benign in DTHD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). Common (popmax 50.7%, afr) — too common for a highly-penetrant pathogenic allele.

DTHD1 p.Ser734=

Q: How common is DTHD1 p.Ser734= (c.2202T>C) in the general population?

DTHD1 p.Ser734= (c.2202T>C) is common (popmax 50.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2202T>C · rs9995922 · VCV1165003

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 50.7%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.48	phastCons 1
Overall
CADD	10.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 50.7% African / African-American · 37,077/73,070 alleles

Filtering AF 50.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 50.1%

Overall 36.5% 566,796/1,551,682 alleles · common exomes 507,321/1,399,580 · genomes 59,475/152,102 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	50.7%	2
Admixed American	37.7%	3
European (non-Finnish)	37.2%	3
Remaining individualsnot grpmax-eligible	35.6%	3
Ashkenazi Jewishnot grpmax-eligible	35.1%	3
Finnishnot grpmax-eligible	34.8%	3
Amishnot grpmax-eligible	31.8%	3
South Asian	25.9%	4
Middle Eastern	24.9%	4
East Asian	18.8%	5

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: DTHD1
Protein: p.Ser734=
Coding: c.2202T>C
MANE Select: NM_001170700
dbSNP: rs9995922
Type: single nucleotide variant
Location: chr4:36316348 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 734: the death domain

Full DTHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTHD1 p.Ser734Ile Uncertain significance ★★ ⚠ same residue
DTHD1 c.1218+1G>A Uncertain significance ★★ same type
DTHD1 c.1219-2A>G Uncertain significance ★★ same type
DTHD1 p.Ala552Ser Uncertain significance ★★ ⚠ same type
DTHD1 p.Ala811Asp Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg326Gln Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg371Cys Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg447Gln 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/dthd1-p-ser734 (accessed [today's date]).

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