Is GANAB p.Ser475Pro (c.1423T>C) pathogenic?

GANAB p.Ser475Pro (c.1423T>C) is classified Uncertain significance in GANAB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). AlphaMissense: likely benign (0.0803); Very rare (popmax 0.00833%, amr).

How common is GANAB p.Ser475Pro (c.1423T>C) in the general population?

GANAB p.Ser475Pro (c.1423T>C) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about GANAB p.Ser475Pro (c.1423T>C)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

GANAB p.Ser475Pro

c.1423T>C · VCV4760631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.568	indeterminate
SaProt	LLR -5.80	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 3.6	GERP 3.3, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,437 bp · p 1e-05 · regional, not allelic
Overall
CADD	17.68	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 0.00833% Admixed American · 5/60,014 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000496% 8/1,614,070 alleles · very rare exomes 7/1,461,850 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,003
European (non-Finnish)	0.000254%	393,346

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: GANAB
Protein: p.Ser475Pro
Coding: c.1423T>C
MANE Select: NM_198334
Type: single nucleotide variant
Location: chr11:62630469 (GRCh38)
Gene constraint: LOEUF 0.391 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.43 · 2 PDB
Residue 475: a β-strand

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

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GANAB p.Arg815Ter Pathogenic/Likely pathogenic ★★ same type
GANAB p.Arg817Trp Likely pathogenic ★★ same type
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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/ganab-p-ser475pro (accessed [today's date]).

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