Is SRMS p.Gln333Arg (c.998A>G) pathogenic?

SRMS p.Gln333Arg (c.998A>G) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: ambiguous (0.3851); Very rare (popmax 0.00364%, amr).

How common is SRMS p.Gln333Arg (c.998A>G) in the general population?

SRMS p.Gln333Arg (c.998A>G) is very rare (popmax 0.00364%, amr) (gnomAD).

What do computational predictors say about SRMS p.Gln333Arg (c.998A>G)?

AlphaMissense predicts ambiguous (score 0.3851) — an in-silico prediction, not a clinical call.

SRMS p.Gln333Arg

c.998A>G · VCV4174856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, amr)

Computational evidence

Protein change
AlphaMissense	0.3851	ambiguous
REVEL	0.474	indeterminate
SaProt	LLR -12.95	damaging
Splicing
SpliceAI	Δ0.58	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	25.3	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 0.00364% Admixed American · 2/54,992 alleles

Filtering AF 0.000603% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000226%

Overall 0.00028% 4/1,427,258 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00364%	27,496
Finnishnot grpmax-eligible	0.00179%	55,928
European (non-Finnish)	8.58e-05%	1,165,869

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: SRMS
Protein: p.Gln333Arg
Coding: c.998A>G
MANE Select: NM_080823
Type: single nucleotide variant
Location: chr20:63541569 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 333: the protein kinase domain

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

Similar variants

SRMS p.Pro382Leu Uncertain significance ★★ ⚠ same type
SRMS p.Pro188= Benign ★★ same type
SRMS p.Ala162Pro Uncertain significance ★ ⚠ same type
SRMS p.Ala175Val Uncertain significance ★ ⚠ same type
SRMS p.Ala199Thr Uncertain significance ★ ⚠ same type
SRMS p.Ala449Gly Uncertain significance ★ ⚠ same type
SRMS p.Ala453Val Uncertain significance ★ ⚠ same type
SRMS p.Ala46Thr Uncertain significance ★ ⚠ 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/srms-p-gln333arg (accessed [today's date]).

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