Is GUCY2C p.Ser300Pro (c.898T>C) pathogenic?

GUCY2C p.Ser300Pro (c.898T>C) is classified Likely benign in GUCY2C (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.0496); Ultra-rare (popmax 0.018%, eas); Associated with Inborn genetic diseases.

What condition is associated with GUCY2C p.Ser300Pro (c.898T>C)?

GUCY2C p.Ser300Pro (c.898T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GUCY2C p.Ser300Pro (c.898T>C) in the general population?

GUCY2C p.Ser300Pro (c.898T>C) is ultra-rare (popmax 0.018%, eas) (gnomAD).

What do computational predictors say about GUCY2C p.Ser300Pro (c.898T>C)?

AlphaMissense predicts likely benign (score 0.0496) — an in-silico prediction, not a clinical call.

GUCY2C p.Ser300Pro

c.898T>C · rs534340677 · VCV2224867

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0496 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0496	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -9.22	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 1.2	GERP -1.2, phastCons 0.32
Regional constraint	o/e 0.89	unconstrained · MANE · 83 kb · p 7.2e-05 · regional, not allelic
Overall
CADD	6.156	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.018% East Asian · 8/44,326 alleles

Filtering AF 0.00893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00648%

Overall 0.000572% 9/1,573,230 alleles · ultra-rare exomes 7/1,421,000 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.018%	5,541
Remaining individualsnot grpmax-eligible	0.00165%	60,618

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: GUCY2C
Protein: p.Ser300Pro
Coding: c.898T>C
MANE Select: NM_004963
dbSNP: rs534340677
Type: single nucleotide variant
Location: chr12:14676904 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.08 · 3 PDB

Full GUCY2C 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

GUCY2C p.Ala450Thr Uncertain significance ★★ ⚠ same condition
GUCY2C p.Ala897Thr Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg1021Cys Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg114Trp Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg319Gln Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg570Gln Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg686Gln Uncertain significance ★★ ⚠ same condition
GUCY2C p.Arg686Trp 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/gucy2c-p-ser300pro (accessed [today's date]).

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