Is DTHD1 p.Arg548Gln (c.1643G>A) pathogenic?

DTHD1 p.Arg548Gln (c.1643G>A) is classified Uncertain significance in DTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.0832); Very rare (popmax 0.00808%, amr).

How common is DTHD1 p.Arg548Gln (c.1643G>A) in the general population?

DTHD1 p.Arg548Gln (c.1643G>A) is very rare (popmax 0.00808%, amr) (gnomAD).

What do computational predictors say about DTHD1 p.Arg548Gln (c.1643G>A)?

AlphaMissense predicts likely benign (score 0.0832) — an in-silico prediction, not a clinical call.

DTHD1 p.Arg548Gln

c.1643G>A · rs769705093 · VCV1367073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00808%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0832	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.48	donor loss · deltas
Pangolin	Δ0.41	loss · gain 0.34 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 62 kb · p 0.66 · regional, not allelic
Overall
CADD	29.6	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 R423Q vs ClinVar R548Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00808% Admixed American · 4/49,478 alleles

Filtering AF 0.00268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00216% 33/1,525,610 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00808%	12,370
Remaining individualsnot grpmax-eligible	0.00681%	14,685
East Asian	0.00493%	20,281
European (non-Finnish)	0.00186%	53,806
African / African-American	0.00138%	72,346
South Asian	0.00123%	81,180

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.Arg548Gln
Coding: c.1643G>A
MANE Select: NM_001170700
dbSNP: rs769705093
Type: single nucleotide variant
Location: chr4:36295039 (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 p.Arg548Trp 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-arg548gln (accessed [today's date]).

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