Is DDHD2 p.Ala461Val (c.1382C>T) pathogenic?

DDHD2 p.Ala461Val (c.1382C>T) is classified Uncertain significance in DDHD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-08). AlphaMissense: likely benign (0.0679); Ultra-rare (popmax 0.0183%, nfe); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Ala461Val (c.1382C>T)?

DDHD2 p.Ala461Val (c.1382C>T) is associated with hereditary spastic paraplegia 54, hereditary spastic paraplegia (ClinVar).

How common is DDHD2 p.Ala461Val (c.1382C>T) in the general population?

DDHD2 p.Ala461Val (c.1382C>T) is ultra-rare (popmax 0.0183%, nfe) (gnomAD).

How is Autosomal recessive spastic paraplegia type 54 inherited?

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

What do computational predictors say about DDHD2 p.Ala461Val (c.1382C>T)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

DDHD2 p.Ala461Val

c.1382C>T · rs201386329 · VCV430398

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -4
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	5.36	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0183% European (non-Finnish) · 216/1,179,996 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0155%

Overall 0.0139% 225/1,614,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0183%	5,463
Remaining individualsnot grpmax-eligible	0.0064%	15,623
African / African-American	0.00534%	18,728
Admixed American	0.00167%	60,006

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.Ala461Val
Coding: c.1382C>T
MANE Select: NM_015214
dbSNP: rs201386329
Type: single nucleotide variant
Location: chr8:38251949 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 461: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the 'disordered' region

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

Also linked: hereditary spastic paraplegia

For Autosomal recessive spastic paraplegia type 54 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DDHD2 c.1126-2A>G Likely pathogenic ★★ same condition
DDHD2 c.1248+2T>C Likely pathogenic ★★ same condition
DDHD2 p.Arg232Ter 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-ala461val (accessed [today's date]).

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