Is DTHD1 p.Phe485Ser (c.1454T>C) pathogenic?

DTHD1 p.Phe485Ser (c.1454T>C) is classified Conflicting classifications of pathogenicity in DTHD1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0817); Very rare (popmax 0.00981%, amr).

How common is DTHD1 p.Phe485Ser (c.1454T>C) in the general population?

DTHD1 p.Phe485Ser (c.1454T>C) is very rare (popmax 0.00981%, amr) (gnomAD).

What do computational predictors say about DTHD1 p.Phe485Ser (c.1454T>C)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

DTHD1 p.Phe485Ser

c.1454T>C · rs1428896067 · VCV1054644

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00981%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -13.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -2.2, phastCons 0.001
Regional constraint	o/e 0.99	unconstrained · MANE · 62 kb · p 0.66 · regional, not allelic
Overall
CADD	8.335	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F360S vs ClinVar F485S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00981% Admixed American · 5/50,950 alleles

Filtering AF 0.00382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00248%

Overall 0.00058% 9/1,550,996 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00981%	10,190
African / African-American	0.00548%	18,257

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.Phe485Ser
Coding: c.1454T>C
MANE Select: NM_001170700
dbSNP: rs1428896067
Type: single nucleotide variant
Location: chr4:36294850 (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-phe485ser (accessed [today's date]).

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