Is DDHD2 p.Arg232Ter (c.694C>T) pathogenic?

DDHD2 p.Arg232Ter (c.694C>T) is classified Pathogenic in DDHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-28). Very rare (popmax 0.0011%, sas); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Arg232Ter (c.694C>T)?

DDHD2 p.Arg232Ter (c.694C>T) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Arg232Ter (c.694C>T) in the general population?

DDHD2 p.Arg232Ter (c.694C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Autosomal recessive spastic paraplegia type 54 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DDHD2 p.Arg232Ter

c.694C>T · rs1249841130 · VCV634496

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary spastic paraplegia 54

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 6 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.30	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.6	GERP -0.078, phastCons 1
Overall
CADD	38.0	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 0.0011% South Asian · 1/90,672 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000311% 5/1,609,714 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,890
South Asiangrpmax	0.0011%	90,672
European (non-Finnish)	0.000255%	392,269

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg232Ter
Coding: c.694C>T
MANE Select: NM_015214
dbSNP: rs1249841130
Type: single nucleotide variant
Location: chr8:38240346 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70

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

Disease context

hereditary spastic paraplegia 54 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 54 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DDHD2 p.Arg232Gln Uncertain significance ★★ ⚠ same residue
DDHD2 c.1126-2A>G Likely pathogenic ★★ same condition
DDHD2 c.1248+2T>C Likely pathogenic ★★ same condition
DDHD2 p.Arg329Ter Pathogenic ★★ same condition
DDHD2 p.Arg516Ter Pathogenic ★★ same condition
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Gln286Ter Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Trp115Ter 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/ddhd2-p-arg232ter (accessed [today's date]).

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