Is DHDH p.Arg127His (c.380G>A) pathogenic?

DHDH p.Arg127His (c.380G>A) is classified Uncertain significance in DHDH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-30). AlphaMissense: ambiguous (0.3961); Rare (popmax 0.118%, sas).

How common is DHDH p.Arg127His (c.380G>A) in the general population?

DHDH p.Arg127His (c.380G>A) is rare (popmax 0.118%, sas) (gnomAD).

What do computational predictors say about DHDH p.Arg127His (c.380G>A)?

AlphaMissense predicts ambiguous (score 0.3961) — an in-silico prediction, not a clinical call.

DHDH p.Arg127His

c.380G>A · VCV4659863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3961 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.118%, sas)

Computational evidence

Protein change
AlphaMissense	0.3961	ambiguous
REVEL	0.549	indeterminate
SaProt	LLR -12.22	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	phastCons 0.87
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.26 · regional, not allelic
Overall
CADD	26.5	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 0.118% South Asian · 107/91,038 alleles

Filtering AF 0.0995% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0927%

Overall 0.00961% 155/1,612,484 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.118%	851
African / African-American	0.0267%	3,749
Middle Eastern	0.0166%	6,020
Remaining individualsnot grpmax-eligible	0.00801%	12,486
East Asian	0.00223%	44,836
European (non-Finnish)	0.0017%	58,937
Admixed American	0.00167%	59,950

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: DHDH
Protein: p.Arg127His
Coding: c.380G>A
MANE Select: NM_014475
Type: single nucleotide variant
Location: chr19:48939462 (GRCh38)
Gene constraint: LOEUF 1.275 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 98.19

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

Similar variants

DHDH p.Ala111Ser Uncertain significance ★ ⚠ same type
DHDH p.Ala134Thr Uncertain significance ★ ⚠ same type
DHDH p.Ala173Thr Uncertain significance ★ ⚠ same type
DHDH p.Ala70Ser Uncertain significance ★ ⚠ same type
DHDH p.Ala89Val Uncertain significance ★ ⚠ same type
DHDH p.Arg107His Uncertain significance ★ ⚠ same type
DHDH p.Arg107Ser Uncertain significance ★ ⚠ same type
DHDH p.Arg136Lys Uncertain significance ★ ⚠ same type

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/dhdh-p-arg127his (accessed [today's date]).

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