Is GDAP1 p.Arg354Ser (c.1062A>T) pathogenic?

GDAP1 p.Arg354Ser (c.1062A>T) is classified Uncertain significance in GDAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-18). AlphaMissense: likely benign (0.1607); Very rare (popmax 0.00769%, sas).

How common is GDAP1 p.Arg354Ser (c.1062A>T) in the general population?

GDAP1 p.Arg354Ser (c.1062A>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about GDAP1 p.Arg354Ser (c.1062A>T)?

AlphaMissense predicts likely benign (score 0.1607) — an in-silico prediction, not a clinical call.

GDAP1 p.Arg354Ser

c.1062A>T · VCV4078761

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1607	likely benign
REVEL	0.67	pathogenic-leaning
SaProt	LLR -6.24	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	21.3	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 0.00769% South Asian · 7/91,078 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000496% 8/1,613,754 alleles · very rare exomes 8/1,461,536 · genomes 0/152,218 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,011
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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.Arg354Ser
Coding: c.1062A>T
MANE Select: NM_018972
Type: single nucleotide variant
Location: chr8:74364352 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 354: the 'required for mitochondrial localization' region

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

Similar variants

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
GDAP1 p.Arg191Ter Pathogenic/Likely pathogenic ★★ same type
GDAP1 p.Arg257Ter 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-arg354ser (accessed [today's date]).

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