Is DHTKD1 p.Pro515Thr (c.1543C>A) pathogenic?

DHTKD1 p.Pro515Thr (c.1543C>A) is classified Likely pathogenic in DHTKD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-08). AlphaMissense: likely benign (0.1669); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2Q.

What condition is associated with DHTKD1 p.Pro515Thr (c.1543C>A)?

DHTKD1 p.Pro515Thr (c.1543C>A) is associated with Charcot-Marie-Tooth disease axonal type 2Q (ClinVar).

How common is DHTKD1 p.Pro515Thr (c.1543C>A) in the general population?

DHTKD1 p.Pro515Thr (c.1543C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DHTKD1 p.Pro515Thr (c.1543C>A)?

AlphaMissense predicts likely benign (score 0.1669) — an in-silico prediction, not a clinical call.

DHTKD1 p.Pro515Thr

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2Q inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1543C>A · rs762729182 · VCV617591

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1669 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease axonal type 2Q

Computational evidence

Protein change
AlphaMissense	0.1669	likely benign ⚠ discordant with ClinVar
REVEL	0.398	indeterminate
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DHTKD1
Protein: p.Pro515Thr
Coding: c.1543C>A
MANE Select: NM_018706
dbSNP: rs762729182
Type: single nucleotide variant
Location: chr10:12097868 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 515: a UniProt-annotated variant site (in aakad); an α-helix

Full DHTKD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2Q — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2Q (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

DHTKD1 p.Pro515Ser Uncertain significance ★ ⚠ same residue
DHTKD1 c.1671+1G>A Likely pathogenic ★★ same condition
DHTKD1 c.1897-1G>A Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 p.Arg410Ter Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 p.Arg455Ter Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 p.Tyr462Ter Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 p.Arg598Cys Uncertain significance ★★ ⚠ same condition
DHTKD1 p.Glu464Gly Uncertain significance ★★ ⚠ same condition

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/dhtkd1-p-pro515thr (accessed [today's date]).

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