Is DDHD2 p.Cys683Ser (c.2047T>A) pathogenic?

DDHD2 p.Cys683Ser (c.2047T>A) is classified Benign/Likely benign in DDHD2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.9094); Rare (popmax 0.278%, nfe); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Cys683Ser (c.2047T>A)?

DDHD2 p.Cys683Ser (c.2047T>A) is associated with hereditary spastic paraplegia 54, hereditary spastic paraplegia (ClinVar).

How common is DDHD2 p.Cys683Ser (c.2047T>A) in the general population?

DDHD2 p.Cys683Ser (c.2047T>A) is rare (popmax 0.278%, 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.Cys683Ser (c.2047T>A)?

AlphaMissense predicts likely pathogenic (score 0.9094) — an in-silico prediction, not a clinical call.

DDHD2 p.Cys683Ser

c.2047T>A · rs148536791 · VCV473072

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9094 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.278%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
AlphaMissense	0.9094	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 6,537 bp · p 8.8e-05 · regional, not allelic
Overall
CADD	25.2	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 0.278% European (non-Finnish) · 3,278/1,179,672 alleles

Filtering AF 0.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.267%

Overall 0.268% 4,323/1,613,460 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.19%	84
European (non-Finnish)grpmax	0.278%	360
Ashkenazi Jewishnot grpmax-eligible	0.267%	374
Remaining individualsnot grpmax-eligible	0.214%	466
African / African-American	0.056%	1,787
Admixed American	0.0468%	2,139
Middle Eastern	0.0165%	6,058

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.Cys683Ser
Coding: c.2047T>A
MANE Select: NM_015214
dbSNP: rs148536791
Type: single nucleotide variant
Location: chr8:38253711 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 683: 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

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-cys683ser (accessed [today's date]).

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