Is DDHD2 p.Thr529Met (c.1586C>T) pathogenic?

DDHD2 p.Thr529Met (c.1586C>T) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-07). AlphaMissense: ambiguous (0.4763); Very rare (popmax 0.0044%, sas); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Thr529Met (c.1586C>T)?

DDHD2 p.Thr529Met (c.1586C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DDHD2 p.Thr529Met (c.1586C>T) in the general population?

DDHD2 p.Thr529Met (c.1586C>T) is very rare (popmax 0.0044%, sas) (gnomAD).

What do computational predictors say about DDHD2 p.Thr529Met (c.1586C>T)?

AlphaMissense predicts ambiguous (score 0.4763) — an in-silico prediction, not a clinical call.

DDHD2 p.Thr529Met

c.1586C>T · rs758497992 · VCV2495072

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4763 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4763	ambiguous
REVEL	0.627	indeterminate
SaProt	LLR -13.16	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	28.8	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

Grpmax group 0.0044% South Asian · 4/90,994 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00171% 25/1,461,568 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,749
East Asian	0.00223%	44,876
European (non-Finnish)	0.0017%	58,996

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: DDHD2
Protein: p.Thr529Met
Coding: c.1586C>T
MANE Select: NM_015214
dbSNP: rs758497992
Type: single nucleotide variant
Location: chr8:38252256 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 529: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the ddhd domain

Full DDHD2 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

Similar variants

DDHD2 p.Thr529= Benign/Likely benign ★★ same residue
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Arg232Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Trp Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg595Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg595Trp 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/ddhd2-p-thr529met (accessed [today's date]).

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