Is GAN p.Ser517Pro (c.1549T>C) pathogenic?

GAN p.Ser517Pro (c.1549T>C) is classified Uncertain significance in GAN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-15). AlphaMissense: likely pathogenic (0.9894); Absent from gnomAD v4.1; Associated with giant axonal neuropathy 1.

What condition is associated with GAN p.Ser517Pro (c.1549T>C)?

GAN p.Ser517Pro (c.1549T>C) is associated with giant axonal neuropathy 1 (ClinVar).

How common is GAN p.Ser517Pro (c.1549T>C) in the general population?

GAN p.Ser517Pro (c.1549T>C) is absent from gnomAD v4.1 (gnomAD).

How is Giant axonal neuropathy inherited?

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

What do computational predictors say about GAN p.Ser517Pro (c.1549T>C)?

AlphaMissense predicts likely pathogenic (score 0.9894) — an in-silico prediction, not a clinical call.

GAN p.Ser517Pro

c.1549T>C · rs1567501233 · VCV571799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9894 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

giant axonal neuropathy 1

Computational evidence

Protein change
AlphaMissense	0.9894	likely pathogenic · top 10% in GAN
REVEL	0.348	indeterminate
SaProt	LLR -11.59	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 62 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	28.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GAN
Protein: p.Ser517Pro
Coding: c.1549T>C
MANE Select: NM_022041
dbSNP: rs1567501233
Type: single nucleotide variant
Location: chr16:81377265 (GRCh38)
Gene constraint: LOEUF 0.842 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.93 · 2 PDB

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

Disease context

giant axonal neuropathy 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Giant axonal neuropathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

GAN p.Ser517Tyr Uncertain significance ★ ⚠ same residue
GAN c.1502+1G>T Pathogenic/Likely pathogenic ★★ same condition
GAN c.851+1G>A Pathogenic/Likely pathogenic ★★ same condition
GAN p.Arg545His Pathogenic/Likely pathogenic ★★ same condition
GAN p.Gln103Ter Pathogenic ★★ same condition
GAN p.Glu486Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
GAN c.1373+4C>T Uncertain significance ★★ same condition
GAN c.1612+4A>G Uncertain significance ★★ 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/gan-p-ser517pro (accessed [today's date]).

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