Is DTHD1 p.Arg548Trp (c.1642C>T) pathogenic?

DTHD1 p.Arg548Trp (c.1642C>T) is classified Uncertain significance in DTHD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-06). AlphaMissense: likely benign (0.0717); Ultra-rare (popmax 0.0197%, eas).

How common is DTHD1 p.Arg548Trp (c.1642C>T) in the general population?

DTHD1 p.Arg548Trp (c.1642C>T) is ultra-rare (popmax 0.0197%, eas) (gnomAD).

What do computational predictors say about DTHD1 p.Arg548Trp (c.1642C>T)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

DTHD1 p.Arg548Trp

c.1642C>T · rs189410090 · VCV844996

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP -4.5
Regional constraint	o/e 0.99	unconstrained · MANE · 62 kb · p 0.66 · regional, not allelic
Overall
CADD	0.835	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R423W vs ClinVar R548W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0197% East Asian · 8/40,580 alleles

Filtering AF 0.00974% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00709%

Overall 0.00779% 119/1,527,606 alleles · ultra-rare exomes 102/1,375,352 · genomes 17/152,254 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0287%	3,486
East Asiangrpmax	0.0197%	5,073
Middle Eastern	0.017%	5,876
Remaining individualsnot grpmax-eligible	0.017%	5,889
Admixed American	0.0121%	8,293
South Asian	0.011%	9,053
European (non-Finnish)	0.00646%	15,492
African / African-American	0.00551%	18,140

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg548Trp
Coding: c.1642C>T
MANE Select: NM_001170700
dbSNP: rs189410090
Type: single nucleotide variant
Location: chr4:36295038 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 423 UniProt numbering: the zu5 2 domain

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

Similar variants

DTHD1 p.Arg548Gln Uncertain significance ★ ⚠ same residue
DTHD1 p.Arg548Gly 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

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-arg548trp (accessed [today's date]).

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