Is GAN p.Pro349Ala (c.1045C>G) pathogenic?

GAN p.Pro349Ala (c.1045C>G) is classified Uncertain significance in GAN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.2911); Very rare (popmax 0.00401%, afr); Associated with giant axonal neuropathy 1.

What condition is associated with GAN p.Pro349Ala (c.1045C>G)?

GAN p.Pro349Ala (c.1045C>G) is associated with giant axonal neuropathy 1 (ClinVar).

How common is GAN p.Pro349Ala (c.1045C>G) in the general population?

GAN p.Pro349Ala (c.1045C>G) is very rare (popmax 0.00401%, afr) (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.Pro349Ala (c.1045C>G)?

AlphaMissense predicts likely benign (score 0.2911) — an in-silico prediction, not a clinical call.

GAN p.Pro349Ala

c.1045C>G · rs374004725 · VCV582736

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

giant axonal neuropathy 1

Computational evidence

Protein change
AlphaMissense	0.2911	likely benign
REVEL	0.626	indeterminate
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 62 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00401% African / African-American · 3/74,872 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000249% 4/1,606,598 alleles · very rare exomes 4/1,454,326 · genomes 0/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,957
European (non-Finnish)	8.52e-05%	1,173,106

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: GAN
Protein: p.Pro349Ala
Coding: c.1045C>G
MANE Select: NM_022041
dbSNP: rs374004725
Type: single nucleotide variant
Location: chr16:81362570 (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.Pro349Ser 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-pro349ala (accessed [today's date]).

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