Is GDAP1 p.Arg41Leu (c.122G>T) pathogenic?

GDAP1 p.Arg41Leu (c.122G>T) is classified Uncertain significance in GDAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-16). AlphaMissense: likely pathogenic (0.9629); Very rare (popmax 0.00267%, afr).

How common is GDAP1 p.Arg41Leu (c.122G>T) in the general population?

GDAP1 p.Arg41Leu (c.122G>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about GDAP1 p.Arg41Leu (c.122G>T)?

AlphaMissense predicts likely pathogenic (score 0.9629) — an in-silico prediction, not a clinical call.

GDAP1 p.Arg41Leu

c.122G>T · VCV4900868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9629	likely pathogenic
REVEL	0.404	indeterminate
SaProt	LLR -10.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,926 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,554 alleles · very rare exomes 3/1,461,360 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,463
East Asian	0.00223%	44,890
European (non-Finnish)	8.48e-05%	1,179,554

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.Arg41Leu
Coding: c.122G>T
MANE Select: NM_018972
Type: single nucleotide variant
Location: chr8:74351278 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 41: the gst n-terminal domain; an α-helix

Full GDAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GDAP1 p.Arg41= Likely benign ★★ same residue
GDAP1 p.Arg41Ser Uncertain significance ★ ⚠ same residue
GDAP1 c.311-1G>A Pathogenic/Likely pathogenic ★★ same type
GDAP1 c.579+1G>A Pathogenic ★★ same type
GDAP1 c.694+1G>A Pathogenic/Likely pathogenic ★★ same type
GDAP1 p.Arg120Trp Pathogenic ★★ ⚠ same type
GDAP1 p.Arg125Ter Pathogenic ★★ same type
GDAP1 p.Arg161His Pathogenic/Likely pathogenic ★★ ⚠ 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/gdap1-p-arg41leu (accessed [today's date]).

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