Is DDHD2 p.Arg422Ter (c.1264C>T) pathogenic?

DDHD2 p.Arg422Ter (c.1264C>T) is classified Likely pathogenic in DDHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-01). Ultra-rare (popmax 0.0168%, mid); Associated with DDHD2-related disorder.

What condition is associated with DDHD2 p.Arg422Ter (c.1264C>T)?

DDHD2 p.Arg422Ter (c.1264C>T) is associated with DDHD2-related disorder (ClinVar).

How common is DDHD2 p.Arg422Ter (c.1264C>T) in the general population?

DDHD2 p.Arg422Ter (c.1264C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

DDHD2 p.Arg422Ter

c.1264C>T · rs746455223 · VCV1202525

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Conditions

DDHD2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.33	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.8	GERP 0.18, phastCons 0.69
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,948 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000549% 8/1,457,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,948
South Asian	0.0022%	45,443
African / African-American	0.00134%	74,818
European (non-Finnish)	0.00034%	294,298

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.Arg422Ter
Coding: c.1264C>T
MANE Select: NM_015214
dbSNP: rs746455223
Type: single nucleotide variant
Location: chr8:38249723 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 422: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the sam domain

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

Disease context

DDHD2-related disorder

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.Arg516Ter Pathogenic ★★ same type
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same type
DDHD2 p.Gln286Ter Pathogenic/Likely pathogenic ★★ same type
DDHD2 p.Trp115Ter 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-arg422ter (accessed [today's date]).

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