Is DTHD1 p.Cys325= (c.975C>T) pathogenic?

DTHD1 p.Cys325= (c.975C>T) is classified Likely benign in DTHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-13). Rare (popmax 0.116%, mid).

How common is DTHD1 p.Cys325= (c.975C>T) in the general population?

DTHD1 p.Cys325= (c.975C>T) is rare (popmax 0.116%, mid) (gnomAD).

DTHD1 p.Cys325=

c.975C>T · rs530789646 · VCV1091362

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

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 1.4	GERP 0.73, phastCons 0.81
Overall
CADD	8.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.116% Middle Eastern · 7/6,018 alleles

Filtering AF 0.0545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0387%

Overall 0.0231% 358/1,551,590 alleles · rare exomes 341/1,399,554 · genomes 17/152,036 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	860
European (non-Finnish)	0.0293%	3,414
Remaining individualsnot grpmax-eligible	0.0199%	5,014
South Asian	0.00357%	28,015

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.Cys325=
Coding: c.975C>T
MANE Select: NM_001170700
dbSNP: rs530789646
Type: single nucleotide variant
Location: chr4:36290460 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 325: the zu5 2 domain

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

Similar variants

DTHD1 p.Cys325Ter 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-cys325 (accessed [today's date]).

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