Is GAN p.Pro359Ser (c.1075C>T) pathogenic?

GAN p.Pro359Ser (c.1075C>T) is classified Uncertain significance in GAN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-13). AlphaMissense: likely benign (0.0682); Very rare (popmax 0.00225%, eas); Associated with Inborn genetic diseases.

What condition is associated with GAN p.Pro359Ser (c.1075C>T)?

GAN p.Pro359Ser (c.1075C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GAN p.Pro359Ser (c.1075C>T) in the general population?

GAN p.Pro359Ser (c.1075C>T) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about GAN p.Pro359Ser (c.1075C>T)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

GAN p.Pro359Ser

c.1075C>T · VCV3280680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.1, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 62 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	20.6	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 0.00225% East Asian · 1/44,496 alleles

Filtering AF 0.000315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000228%

Overall 0.000724% 11/1,518,716 alleles · very rare exomes 10/1,366,530 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,496
Remaining individualsnot grpmax-eligible	0.00169%	59,144
South Asian	0.00112%	89,168
European (non-Finnish)	0.000732%	136,619

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.Pro359Ser
Coding: c.1075C>T
MANE Select: NM_022041
Type: single nucleotide variant
Location: chr16:81362600 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GAN c.851+1G>A Pathogenic/Likely pathogenic ★★ same condition
GAN p.Glu486Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
GAN c.1373+4C>T Uncertain significance ★★ same condition
GAN c.283-3T>A Uncertain significance ★★ same condition
GAN p.Ala418Pro Uncertain significance ★★ ⚠ same condition
GAN p.Ala425Thr Uncertain significance ★★ ⚠ same condition
GAN p.Ala461Thr Uncertain significance ★★ ⚠ same condition
GAN p.Ala572Gly 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-pro359ser (accessed [today's date]).

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