Is DTHD1 p.Lys556= (c.1668A>G) pathogenic?

DTHD1 p.Lys556= (c.1668A>G) is classified Likely benign in DTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-13). Ultra-rare (popmax 0.0246%, afr).

How common is DTHD1 p.Lys556= (c.1668A>G) in the general population?

DTHD1 p.Lys556= (c.1668A>G) is ultra-rare (popmax 0.0246%, afr) (gnomAD).

DTHD1 p.Lys556=

c.1668A>G · rs569199264 · VCV1101025

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, afr)

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 1.2	GERP -1.8, phastCons 0.99
Overall
CADD	0.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0246% African / African-American · 18/73,134 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.00187% 29/1,551,828 alleles · ultra-rare exomes 15/1,399,558 · genomes 14/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0246%	4,063
Admixed American	0.0137%	7,285
Remaining individualsnot grpmax-eligible	0.00498%	20,062
South Asian	0.00119%	84,028

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.Lys556=
Coding: c.1668A>G
MANE Select: NM_001170700
dbSNP: rs569199264
Type: single nucleotide variant
Location: chr4:36306215 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99

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-lys556 (accessed [today's date]).

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