Is DTHD1 p.Asp728= (c.2184C>T) pathogenic?

DTHD1 p.Asp728= (c.2184C>T) is classified Likely benign in DTHD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00589%, amr).

How common is DTHD1 p.Asp728= (c.2184C>T) in the general population?

DTHD1 p.Asp728= (c.2184C>T) is very rare (popmax 0.00589%, amr) (gnomAD).

DTHD1 p.Asp728=

c.2184C>T · rs377400926 · VCV1159104

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00589%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Overall
CADD	12.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00589% Admixed American · 3/50,970 alleles

Filtering AF 0.00439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00399%

Overall 0.00464% 72/1,551,876 alleles · very rare exomes 62/1,399,760 · genomes 10/152,116 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00589%	16,990
European (non-Finnish)	0.00549%	18,207
African / African-American	0.00548%	18,253
Remaining individualsnot grpmax-eligible	0.00332%	30,103

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.Asp728=
Coding: c.2184C>T
MANE Select: NM_001170700
dbSNP: rs377400926
Type: single nucleotide variant
Location: chr4:36316330 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 728: the death domain

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

Similar variants

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
DTHD1 p.Arg447Ter 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-asp728 (accessed [today's date]).

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