Is GDAP1 p.Ser169Phe (c.506C>T) pathogenic?

GDAP1 p.Ser169Phe (c.506C>T) is classified Uncertain significance in GDAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-18). AlphaMissense: likely benign (0.2884); Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease type 4A.

What condition is associated with GDAP1 p.Ser169Phe (c.506C>T)?

GDAP1 p.Ser169Phe (c.506C>T) is associated with Charcot-Marie-Tooth disease type 4A (ClinVar).

How common is GDAP1 p.Ser169Phe (c.506C>T) in the general population?

GDAP1 p.Ser169Phe (c.506C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Charcot-Marie-Tooth disease type 4A inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GDAP1 p.Ser169Phe (c.506C>T)?

AlphaMissense predicts likely benign (score 0.2884) — an in-silico prediction, not a clinical call.

GDAP1 p.Ser169Phe

c.506C>T · rs779770529 · VCV1896151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth disease type 4A

Computational evidence

Protein change
AlphaMissense	0.2884	likely benign
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -8.56	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 6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 14 kb · p 0.0041 · regional, not allelic
Overall
CADD	26.1	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 0.00223% East Asian · 1/44,800 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000312% 5/1,602,148 alleles · very rare exomes 5/1,449,870 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,800
South Asian	0.0011%	90,914
European (non-Finnish)	0.000257%	389,675

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.Ser169Phe
Coding: c.506C>T
MANE Select: NM_018972
dbSNP: rs779770529
Type: single nucleotide variant
Location: chr8:74361905 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.68 · 8 PDB
Residue 169: the gst c-terminal domain

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

Disease context

Charcot-Marie-Tooth disease type 4A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 4A (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GDAP1 p.Ser169= Benign ★★ same residue
GDAP1 p.Ser169Leu Uncertain significance ★★ 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-ser169phe (accessed [today's date]).

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