Is DDHD2 p.Arg295His (c.884G>A) pathogenic?

DDHD2 p.Arg295His (c.884G>A) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-18). AlphaMissense: likely pathogenic (0.7372); Very rare (popmax 0.0011%, sas).

How common is DDHD2 p.Arg295His (c.884G>A) in the general population?

DDHD2 p.Arg295His (c.884G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DDHD2 p.Arg295His (c.884G>A)?

AlphaMissense predicts likely pathogenic (score 0.7372) — an in-silico prediction, not a clinical call.

DDHD2 p.Arg295His

c.884G>A · rs561561545 · VCV1336192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7372 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7372	likely pathogenic
REVEL	0.79	moderately pathogenic-leaning
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	27.6	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 0.0011% South Asian · 1/91,086 alleles

Overall 0.000137% 2/1,461,822 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	8.47e-05%	1,180,011

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.Arg295His
Coding: c.884G>A
MANE Select: NM_015214
dbSNP: rs561561545
Type: single nucleotide variant
Location: chr8:38245777 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 295: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity)

Full DDHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DDHD2 c.1126-2A>G Likely pathogenic ★★ same type
DDHD2 c.1248+2T>C Likely pathogenic ★★ same type
DDHD2 p.Arg232Ter Pathogenic ★★ same type
DDHD2 p.Arg329Ter Pathogenic ★★ same type
DDHD2 p.Arg422Ter Likely pathogenic ★★ same type
DDHD2 p.Arg516Ter Pathogenic ★★ same type
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same type
DDHD2 p.Gln286Ter Pathogenic/Likely pathogenic ★★ 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/ddhd2-p-arg295his (accessed [today's date]).

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