Is DDHD2 p.Asp376Gly (c.1127A>G) pathogenic?

DDHD2 p.Asp376Gly (c.1127A>G) is classified Benign/Likely benign in DDHD2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0607); Rare (popmax 0.502%, nfe); Associated with hereditary spastic paraplegia.

What condition is associated with DDHD2 p.Asp376Gly (c.1127A>G)?

DDHD2 p.Asp376Gly (c.1127A>G) is associated with hereditary spastic paraplegia, hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Asp376Gly (c.1127A>G) in the general population?

DDHD2 p.Asp376Gly (c.1127A>G) is rare (popmax 0.502%, nfe) (gnomAD).

What do computational predictors say about DDHD2 p.Asp376Gly (c.1127A>G)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

DDHD2 p.Asp376Gly

c.1127A>G · rs148664622 · VCV210838

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.502%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -7.22	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 0.26	GERP -3.7
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	12.95	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 0.502% European (non-Finnish) · 5,587/1,111,896 alleles

Filtering AF 0.491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.487%

Overall 0.415% 6,182/1,489,866 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.502%	199
Remaining individualsnot grpmax-eligible	0.444%	225
Finnishnot grpmax-eligible	0.325%	308
Admixed American	0.196%	509
African / African-American	0.0847%	1,180
Ashkenazi Jewishnot grpmax-eligible	0.00775%	12,895
South Asian	0.00132%	75,520

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.Asp376Gly
Coding: c.1127A>G
MANE Select: NM_015214
dbSNP: rs148664622
Type: single nucleotide variant
Location: chr8:38247714 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 376: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity)

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

Disease context

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

Also linked: hereditary spastic paraplegia 54

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-asp376gly (accessed [today's date]).

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