Is DDHD2 p.Gly76Asp (c.227G>A) pathogenic?

DDHD2 p.Gly76Asp (c.227G>A) is classified Benign/Likely benign in DDHD2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0521); Rare (popmax 0.904%, afr); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Gly76Asp (c.227G>A)?

DDHD2 p.Gly76Asp (c.227G>A) is associated with Inborn genetic diseases, hereditary spastic paraplegia 54, hereditary spastic paraplegia (ClinVar).

How common is DDHD2 p.Gly76Asp (c.227G>A) in the general population?

DDHD2 p.Gly76Asp (c.227G>A) is rare (popmax 0.904%, afr) (gnomAD).

What do computational predictors say about DDHD2 p.Gly76Asp (c.227G>A)?

AlphaMissense predicts likely benign (score 0.0521) — an in-silico prediction, not a clinical call.

DDHD2 p.Gly76Asp

c.227G>A · rs150361106 · VCV701940

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0521 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.904%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0521	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -3.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	11.56	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 0.904% African / African-American · 659/72,912 alleles

Filtering AF 0.847% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.824%

Overall 0.0846% 1,334/1,577,418 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.904%	111
Middle Eastern	0.337%	297
Ashkenazi Jewishnot grpmax-eligible	0.243%	412
Admixed American	0.215%	464
Remaining individualsnot grpmax-eligible	0.172%	580
Amishnot grpmax-eligible	0.11%	912
European (non-Finnish)	0.03%	3,339
South Asian	0.0297%	3,364

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.Gly76Asp
Coding: c.227G>A
MANE Select: NM_015214
dbSNP: rs150361106
Type: single nucleotide variant
Location: chr8:38234400 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 76: the wwe domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 54 hereditary spastic paraplegia

Similar variants

DDHD2 p.Gly76Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
DDHD2 p.Gly76Tyr Conflicting classifications of pathogenicity ★ same residue
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

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-gly76asp (accessed [today's date]).

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