Is GLS p.Ser73Pro (c.217T>C) pathogenic?

GLS p.Ser73Pro (c.217T>C) is classified Uncertain significance in GLS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-01). AlphaMissense: likely benign (0.0752); Very rare (popmax 8.93e-05%, nfe).

How common is GLS p.Ser73Pro (c.217T>C) in the general population?

GLS p.Ser73Pro (c.217T>C) is very rare (popmax 8.93e-05%, nfe) (gnomAD).

What do computational predictors say about GLS p.Ser73Pro (c.217T>C)?

AlphaMissense predicts likely benign (score 0.0752) — an in-silico prediction, not a clinical call.

GLS p.Ser73Pro

c.217T>C · rs2470211735 · VCV2651764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.93e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0752	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 1.2, phastCons 1
Overall
CADD	20.7	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 8.93e-05% European (non-Finnish) · 1/1,120,320 alleles

Overall 7.47e-05% 1/1,338,586 alleles · very rare

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: GLS
Protein: p.Ser73Pro
Coding: c.217T>C
MANE Select: NM_013267 · reported on NM_014905
dbSNP: rs2470211735
Type: single nucleotide variant
Location: chr2:190881301 (GRCh38)
Structure: AlphaFold pLDDT 85.66 · 4 PDB
Residue 73: an α-helix

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

Similar variants

GLS p.Ser73Phe Uncertain significance ★ ⚠ same residue
GLS p.Ala99Thr Uncertain significance ★★ ⚠ same type
GLS p.Leu25Arg Uncertain significance ★★ ⚠ same type
GLS c.387-3T>C Likely benign ★★ same type
GLS p.Ala561= Benign ★★ same type
GLS p.Arg53= Likely benign ★★ same type
GLS p.Pro313= Likely benign ★★ same type
GLS p.Val554= Likely benign ★★ 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/gls-p-ser73pro (accessed [today's date]).

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