Is GSN p.Pro481Ser (c.1441C>T) pathogenic?

GSN p.Pro481Ser (c.1441C>T) is classified Uncertain significance in GSN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.7607); Very rare (popmax 0.0011%, sas).

How common is GSN p.Pro481Ser (c.1441C>T) in the general population?

GSN p.Pro481Ser (c.1441C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about GSN p.Pro481Ser (c.1441C>T)?

AlphaMissense predicts likely pathogenic (score 0.7607) — an in-silico prediction, not a clinical call.

GSN p.Pro481Ser

c.1441C>T · rs1468193571 · VCV2879087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7607	likely pathogenic
REVEL	0.497	indeterminate
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; 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 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 31 kb · p 8.7e-05 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P532S vs ClinVar P481S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,070 alleles

Overall 0.000124% 2/1,614,060 alleles · very rare exomes 2/1,461,684 · genomes 0/152,376 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,180,022

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: GSN
Protein: p.Pro481Ser
Coding: c.1441C>T
MANE Select: NM_198252
dbSNP: rs1468193571
Type: single nucleotide variant
Location: chr9:121326536 (GRCh38)
Gene constraint: LOEUF 0.788 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.76 · 65 PDB
Residue 532 UniProt numbering: the 'actin-binding, ca-sensitive' region

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

Similar variants

GSN p.Pro481Thr Uncertain significance ★★ ⚠ same residue
GSN p.Pro481= Likely benign ★ same residue
GSN p.Asn160Lys Pathogenic ★★ same type
GSN p.Asp163Asn Pathogenic/Likely pathogenic ★★ same type
GSN p.Asp163Tyr Pathogenic/Likely pathogenic ★★ same type
GSN c.1762+2T>C Uncertain significance ★★ same type
GSN c.513+1G>A Uncertain significance ★★ same type
GSN c.753+1G>A Uncertain significance ★★ same type

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/gsn-p-pro481ser (accessed [today's date]).

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