Is RYR1 p.Ser2000Phe (c.5999C>T) pathogenic?

RYR1 p.Ser2000Phe (c.5999C>T) is classified Uncertain significance in RYR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-27). AlphaMissense: likely pathogenic (0.8998); Very rare (popmax 0.00161%, nfe); Associated with congenital fiber-type disproportion myopathy.

What condition is associated with RYR1 p.Ser2000Phe (c.5999C>T)?

RYR1 p.Ser2000Phe (c.5999C>T) is associated with congenital fiber-type disproportion myopathy (ClinVar).

How common is RYR1 p.Ser2000Phe (c.5999C>T) in the general population?

RYR1 p.Ser2000Phe (c.5999C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

How is Congenital fiber-type disproportion myopathy inherited?

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

What do computational predictors say about RYR1 p.Ser2000Phe (c.5999C>T)?

AlphaMissense predicts likely pathogenic (score 0.8998) — an in-silico prediction, not a clinical call.

RYR1 p.Ser2000Phe

c.5999C>T · rs750324313 · VCV931243

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Conditions

congenital fiber-type disproportion myopathy

Computational evidence

Protein change
AlphaMissense	0.8998	likely pathogenic
REVEL	0.445	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 49 kb · p 8.1e-10 · regional, not allelic
Overall
CADD	23.0	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 0.00161% European (non-Finnish) · 19/1,179,946 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,613,834 alleles · very rare exomes 18/1,461,594 · genomes 1/152,240 · 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.Ser2000Phe
Coding: c.5999C>T
MANE Select: NM_000540
dbSNP: rs750324313
Type: single nucleotide variant
Location: chr19:38490260 (GRCh38)
Gene constraint: LOEUF 0.644 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2000: the '6 x approximate repeats' region

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

Disease context

congenital fiber-type disproportion myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital fiber-type disproportion myopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

RYR1 c.10347+1G>A Pathogenic ★★★ same condition
RYR1 c.9472+1G>A Pathogenic ★★★ same condition
RYR1 p.Arg2508Cys Likely pathogenic ★★★ same condition
RYR1 p.Arg4737Gln Pathogenic ★★★ same condition
RYR1 p.Asp2431Tyr Likely pathogenic ★★★ same condition
RYR1 p.Cys3402Gly Pathogenic ★★★ same condition
RYR1 p.Ser1728Phe Likely pathogenic ★★★ same condition
RYR1 c.14364+1G>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/ryr1-p-ser2000phe (accessed [today's date]).

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