Is DDHD2 p.Val170Met (c.508G>A) pathogenic?

DDHD2 p.Val170Met (c.508G>A) is classified Uncertain significance in DDHD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-17). AlphaMissense: likely pathogenic (0.6193); Very rare (popmax 0.00222%, sas); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Val170Met (c.508G>A)?

DDHD2 p.Val170Met (c.508G>A) is associated with Inborn genetic diseases, hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Val170Met (c.508G>A) in the general population?

DDHD2 p.Val170Met (c.508G>A) is very rare (popmax 0.00222%, sas) (gnomAD).

What do computational predictors say about DDHD2 p.Val170Met (c.508G>A)?

AlphaMissense predicts likely pathogenic (score 0.6193) — an in-silico prediction, not a clinical call.

DDHD2 p.Val170Met

c.508G>A · rs754889897 · VCV2058487

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6193	likely pathogenic
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	23.2	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 0.00222% South Asian · 2/90,144 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00124% 20/1,609,888 alleles · very rare exomes 16/1,457,674 · genomes 4/152,214 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00222%	45,072
Remaining individualsnot grpmax-eligible	0.00161%	62,286
European (non-Finnish)	0.00136%	73,674
African / African-American	0.00134%	74,734

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.Val170Met
Coding: c.508G>A
MANE Select: NM_015214
dbSNP: rs754889897
Type: single nucleotide variant
Location: chr8:38238095 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70

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 p.Val170Leu Uncertain significance ★ ⚠ same residue
PLPP5 p.Lys170Asn Uncertain significance ★ ⚠ 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-val170met (accessed [today's date]).

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