Is DHTKD1 p.Pro706Ser (c.2116C>T) pathogenic?

DHTKD1 p.Pro706Ser (c.2116C>T) is classified Uncertain significance in DHTKD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-29). AlphaMissense: ambiguous (0.4377); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with DHTKD1 p.Pro706Ser (c.2116C>T)?

DHTKD1 p.Pro706Ser (c.2116C>T) is associated with Inborn genetic diseases, 2-aminoadipic 2-oxoadipic aciduria (ClinVar).

How common is DHTKD1 p.Pro706Ser (c.2116C>T) in the general population?

DHTKD1 p.Pro706Ser (c.2116C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about DHTKD1 p.Pro706Ser (c.2116C>T)?

AlphaMissense predicts ambiguous (score 0.4377) — an in-silico prediction, not a clinical call.

DHTKD1 p.Pro706Ser

c.2116C>T · rs763819099 · VCV2973101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4377	ambiguous
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -12.78	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.97, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 52 kb · p 0.072 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 0.00667% Admixed American · 4/59,996 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000547% 8/1,461,652 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
European (non-Finnish)	0.000339%	294,960

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: DHTKD1
Protein: p.Pro706Ser
Coding: c.2116C>T
MANE Select: NM_018706
dbSNP: rs763819099
Type: single nucleotide variant
Location: chr10:12107977 (GRCh38)
Gene constraint: LOEUF 0.864 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.19 · 8 PDB
Residue 706: a UniProt-annotated variant site (in aakad)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 2-aminoadipic 2-oxoadipic aciduria

Similar variants

DHTKD1 c.1671+1G>A Likely pathogenic ★★ same condition
DHTKD1 c.1897-1G>A Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 c.2320-2A>T Likely pathogenic ★★ same condition
DHTKD1 c.2572+1G>A Likely pathogenic ★★ same condition
DHTKD1 p.Arg163Ter Pathogenic ★★ same condition
DHTKD1 p.Arg410Ter Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 p.Arg455Ter Pathogenic/Likely pathogenic ★★ same condition
DHTKD1 p.Arg712Ter Pathogenic/Likely pathogenic ★★ 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-pro706ser (accessed [today's date]).

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