Is DDHD2 p.Val691Ala (c.2072T>C) pathogenic?

DDHD2 p.Val691Ala (c.2072T>C) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-21). AlphaMissense: likely benign (0.228); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Val691Ala (c.2072T>C)?

DDHD2 p.Val691Ala (c.2072T>C) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Val691Ala (c.2072T>C) in the general population?

DDHD2 p.Val691Ala (c.2072T>C) is absent from gnomAD v4.1 (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.Val691Ala (c.2072T>C)?

AlphaMissense predicts likely benign (score 0.228) — an in-silico prediction, not a clinical call.

DDHD2 p.Val691Ala

c.2072T>C · rs2487070174 · VCV2045634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.228 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
AlphaMissense	0.228	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -6.18	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 5.1	GERP -1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 6,537 bp · p 8.8e-05 · regional, not allelic
Overall
CADD	18.46	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DDHD2
Protein: p.Val691Ala
Coding: c.2072T>C
MANE Select: NM_015214
dbSNP: rs2487070174
Type: single nucleotide variant
Location: chr8:38260057 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 691: 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

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 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-val691ala (accessed [today's date]).

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