Is GSN p.Phe705= (c.2115T>C) pathogenic?

GSN p.Phe705= (c.2115T>C) is classified Benign in GSN (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 24.6%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Finnish type amyloidosis.

What condition is associated with GSN p.Phe705= (c.2115T>C)?

GSN p.Phe705= (c.2115T>C) is associated with Finnish type amyloidosis (ClinVar).

How is AGel amyloidosis inherited?

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

GSN p.Phe705=

Q: How common is GSN p.Phe705= (c.2115T>C) in the general population?

GSN p.Phe705= (c.2115T>C) is common (popmax 24.6%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2115T>C · rs9102 · VCV364830

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 24.6%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

Finnish type amyloidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.7	GERP -3.8
Overall
CADD	1.532	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 24.6% Admixed American · 14,738/60,002 alleles

Filtering AF 24.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.1%

Overall 3.29% 53,165/1,613,976 alleles · common exomes 42,298/1,461,804 · genomes 10,867/152,172 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	24.6%	4
East Asian	14.9%	7
African / African-American	14.8%	7
South Asian	6.85%	15
Remaining individualsnot grpmax-eligible	3.81%	26
Finnishnot grpmax-eligible	2.78%	36
Ashkenazi Jewishnot grpmax-eligible	2.43%	41
Middle Eastern	1.63%	61
European (non-Finnish)	0.801%	125

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.Phe705=
Coding: c.2115T>C
MANE Select: NM_198252
dbSNP: rs9102
Type: single nucleotide variant
Location: chr9:121332522 (GRCh38)
Gene constraint: LOEUF 0.788 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.76 · 65 PDB
Residue 705: the 'actin-binding, ca-sensitive' region

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

Disease context

Finnish type amyloidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For AGel amyloidosis (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

GSN p.Asn160Lys Pathogenic ★★ same condition
GSN p.Asp163Asn Pathogenic/Likely pathogenic ★★ same condition
GSN p.Asp163Tyr Pathogenic/Likely pathogenic ★★ same condition
GSN c.1762+2T>C Uncertain significance ★★ same condition
GSN c.513+1G>A Uncertain significance ★★ same condition
GSN c.753+1G>A Uncertain significance ★★ same condition
GSN c.754-1G>T Uncertain significance ★★ same condition
GSN c.-9-1981C>T 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/gsn-p-phe705 (accessed [today's date]).

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