Is DDHD2 p.Arg230His (c.689G>A) pathogenic?

DDHD2 p.Arg230His (c.689G>A) is classified Uncertain significance in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.4334); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with DDHD2 p.Arg230His (c.689G>A)?

DDHD2 p.Arg230His (c.689G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DDHD2 p.Arg230His (c.689G>A) in the general population?

DDHD2 p.Arg230His (c.689G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DDHD2 p.Arg230His (c.689G>A)?

AlphaMissense predicts ambiguous (score 0.4334) — an in-silico prediction, not a clinical call.

DDHD2 p.Arg230His

c.689G>A · VCV4238376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4334 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4334	ambiguous
REVEL	0.314	indeterminate
SaProt	LLR -10.98	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 21 kb · p 0.01 · regional, not allelic
Overall
CADD	33.0	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 0.00333% Admixed American · 2/59,976 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000651%

Overall 0.00149% 24/1,610,026 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,988
South Asian	0.00331%	30,231
East Asian	0.00223%	44,794
Remaining individualsnot grpmax-eligible	0.00161%	62,294
European (non-Finnish)	0.00136%	73,562
African / African-American	0.00133%	74,958

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.Arg230His
Coding: c.689G>A
MANE Select: NM_015214
Type: single nucleotide variant
Location: chr8:38240341 (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

Similar variants

DDHD2 p.Arg230Cys Uncertain significance ★★ ⚠ same residue
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Arg232Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg329Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg494Trp Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg595Gln Uncertain significance ★★ ⚠ same condition
DDHD2 p.Arg595Trp Uncertain significance ★★ 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-arg230his (accessed [today's date]).

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