Is RYR1 p.Ser1663Trp (c.4988C>G) pathogenic?

RYR1 p.Ser1663Trp (c.4988C>G) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-01). AlphaMissense: likely benign (0.1504); Very rare (popmax 0.00017%, nfe).

How common is RYR1 p.Ser1663Trp (c.4988C>G) in the general population?

RYR1 p.Ser1663Trp (c.4988C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about RYR1 p.Ser1663Trp (c.4988C>G)?

AlphaMissense predicts likely benign (score 0.1504) — an in-silico prediction, not a clinical call.

RYR1 p.Ser1663Trp

c.4988C>G · rs1969242788 · VCV3026347

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
AlphaMissense	0.1504	likely benign
REVEL	0.502	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -4.2, phastCons 0.98
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 8.1e-10 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,944 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,610,620 alleles · very rare exomes 2/1,458,294 · genomes 0/152,326 · 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: RYR1
Protein: p.Ser1663Trp
Coding: c.4988C>G
MANE Select: NM_000540
dbSNP: rs1969242788
Type: single nucleotide variant
Location: chr19:38485643 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1663: the '6 x approximate repeats' region

Full RYR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RYR1 p.Ser1663= Likely benign ★ same residue
RYR1 c.10347+1G>A Pathogenic ★★★ same type
RYR1 c.10348-6C>G Pathogenic ★★★ same type
RYR1 c.1925+1G>C Likely pathogenic ★★★ same type
RYR1 c.8310+1G>T Pathogenic ★★★ same type
RYR1 c.9472+1G>A Pathogenic ★★★ same type
RYR1 p.Ala152Asp Likely pathogenic ★★★ same type
RYR1 p.Ala2200Val Likely pathogenic ★★★ ⚠ 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/ryr1-p-ser1663trp (accessed [today's date]).

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