Is GSS p.Pro413Ser (c.1237C>T) pathogenic?

GSS p.Pro413Ser (c.1237C>T) is classified Uncertain significance in GSS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.1435); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GSS p.Pro413Ser (c.1237C>T)?

GSS p.Pro413Ser (c.1237C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GSS p.Pro413Ser (c.1237C>T) in the general population?

GSS p.Pro413Ser (c.1237C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about GSS p.Pro413Ser (c.1237C>T)?

AlphaMissense predicts likely benign (score 0.1435) — an in-silico prediction, not a clinical call.

GSS p.Pro413Ser

c.1237C>T · rs2519016756 · VCV2235378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1435	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 23 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	18.36	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 8.48e-05% European (non-Finnish) · 1/1,179,908 alleles

Overall 6.2e-05% 1/1,614,076 alleles · very rare exomes 1/1,461,762 · genomes 0/152,314 · joint denominator

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: GSS
Protein: p.Pro413Ser
Coding: c.1237C>T
MANE Select: NM_000178
dbSNP: rs2519016756
Type: single nucleotide variant
Location: chr20:34929465 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.25 · 2 PDB

Full GSS 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

GSS p.Pro413= Likely benign ★ same residue
GSS p.Arg132Cys Uncertain significance ★★ ⚠ same condition
GSS p.Arg158Trp Uncertain significance ★★ ⚠ same condition
GSS p.Arg25Trp Uncertain significance ★★ ⚠ same condition
GSS p.Arg360Trp Uncertain significance ★★ ⚠ same condition
GSS p.Glu281Gly Uncertain significance ★★ ⚠ same condition
GSS p.Gly136Val Uncertain significance ★★ ⚠ same condition
GSS p.Gly427Ser 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/gss-p-pro413ser (accessed [today's date]).

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