Is GDAP1 p.Arg282His (c.845G>A) pathogenic?

GDAP1 p.Arg282His (c.845G>A) is classified Pathogenic in GDAP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.3262); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with GDAP1 p.Arg282His (c.845G>A)?

GDAP1 p.Arg282His (c.845G>A) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease type 4A, Charcot-Marie-Tooth disease (ClinVar).

How common is GDAP1 p.Arg282His (c.845G>A) in the general population?

GDAP1 p.Arg282His (c.845G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about GDAP1 p.Arg282His (c.845G>A)?

AlphaMissense predicts likely benign (score 0.3262) — an in-silico prediction, not a clinical call.

GDAP1 p.Arg282His

c.845G>A · rs375431837 · VCV574996

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3262 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3262	likely benign ⚠ discordant with ClinVar
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00118% 19/1,614,056 alleles · ultra-rare exomes 16/1,461,888 · genomes 3/152,168 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00534%	18,728
East Asian	0.00223%	44,898
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,084
European (non-Finnish)	0.000932%	107,277

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: GDAP1
Protein: p.Arg282His
Coding: c.845G>A
MANE Select: NM_018972
dbSNP: rs375431837
Type: single nucleotide variant
Location: chr8:74364135 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 282: a UniProt-annotated variant site (in cmtria; no effect on mitochondrial localization but impairment in the ability to induce mitochondrial fragmentation); a UniProt-annotated variant site (in cmt2k; recessive form); the gst c-terminal domain; an α-helix

Full GDAP1 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: Charcot-Marie-Tooth disease type 4A Charcot-Marie-Tooth disease

Similar variants

GDAP1 p.Arg282Cys Pathogenic ★★ same residue
GDAP1 p.Arg282= Likely benign ★ same residue
GDAP1 c.311-1G>A Pathogenic/Likely pathogenic ★★ same condition
GDAP1 c.579+1G>A Pathogenic ★★ same condition
GDAP1 c.694+1G>A Pathogenic/Likely pathogenic ★★ same condition
GDAP1 p.Arg120Trp Pathogenic ★★ ⚠ same condition
GDAP1 p.Arg125Ter Pathogenic ★★ same condition
GDAP1 p.Arg161His 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/gdap1-p-arg282his (accessed [today's date]).

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