Is DDHD2 p.Phe502Leu (c.1504T>C) pathogenic?

DDHD2 p.Phe502Leu (c.1504T>C) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: likely pathogenic (0.9051); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Phe502Leu (c.1504T>C)?

DDHD2 p.Phe502Leu (c.1504T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DDHD2 p.Phe502Leu (c.1504T>C) in the general population?

DDHD2 p.Phe502Leu (c.1504T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about DDHD2 p.Phe502Leu (c.1504T>C)?

AlphaMissense predicts likely pathogenic (score 0.9051) — an in-silico prediction, not a clinical call.

DDHD2 p.Phe502Leu

c.1504T>C · VCV4009992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9051 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9051	likely pathogenic
REVEL	0.362	indeterminate
SaProt	LLR -10.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,044 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,068 alleles · very rare

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.Phe502Leu
Coding: c.1504T>C
MANE Select: NM_015214
Type: single nucleotide variant
Location: chr8:38252174 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 502: 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.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
DDHD2 p.Gly449Cys 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-phe502leu (accessed [today's date]).

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