Is DDHD2 p.Thr625Pro (c.1873A>C) pathogenic?

DDHD2 p.Thr625Pro (c.1873A>C) is classified Uncertain significance in DDHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-04). AlphaMissense: likely benign (0.0599); Ultra-rare (popmax 0.021%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Thr625Pro (c.1873A>C)?

DDHD2 p.Thr625Pro (c.1873A>C) is associated with Inborn genetic diseases, hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Thr625Pro (c.1873A>C) in the general population?

DDHD2 p.Thr625Pro (c.1873A>C) is ultra-rare (popmax 0.021%, nfe) (gnomAD).

What do computational predictors say about DDHD2 p.Thr625Pro (c.1873A>C)?

AlphaMissense predicts likely benign (score 0.0599) — an in-silico prediction, not a clinical call.

DDHD2 p.Thr625Pro

c.1873A>C · rs369779587 · VCV648161

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0599 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0599	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.53	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 1.2	GERP -1.4, phastCons 0.11
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	14.53	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 0.021% European (non-Finnish) · 248/1,179,858 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.0156% 252/1,613,738 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.021%	4,757
Remaining individualsnot grpmax-eligible	0.0032%	31,235
Finnishnot grpmax-eligible	0.00156%	64,022
African / African-American	0.00133%	74,918

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.Thr625Pro
Coding: c.1873A>C
MANE Select: NM_015214
dbSNP: rs369779587
Type: single nucleotide variant
Location: chr8:38253109 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 625: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the ddhd domain; the 'disordered' region

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

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-thr625pro (accessed [today's date]).

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