Is SRMS p.Arg349Gln (c.1046G>A) pathogenic?

SRMS p.Arg349Gln (c.1046G>A) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-22). AlphaMissense: ambiguous (0.3446); Very rare (popmax 0.00341%, amr).

How common is SRMS p.Arg349Gln (c.1046G>A) in the general population?

SRMS p.Arg349Gln (c.1046G>A) is very rare (popmax 0.00341%, amr) (gnomAD).

What do computational predictors say about SRMS p.Arg349Gln (c.1046G>A)?

AlphaMissense predicts ambiguous (score 0.3446) — an in-silico prediction, not a clinical call.

SRMS p.Arg349Gln

c.1046G>A · rs1361962678 · VCV3170004

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3446 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00341%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3446	ambiguous
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -12.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP 1.9, phastCons 0.88
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	26.9	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 0.00341% Admixed American · 2/58,708 alleles

Filtering AF 0.000565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00043%

Overall 0.000936% 15/1,602,790 alleles · very rare exomes 15/1,450,468 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00341%	29,354
South Asian	0.00111%	90,202
European (non-Finnish)	0.00102%	98,030

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.Arg349Gln
Coding: c.1046G>A
MANE Select: NM_080823
dbSNP: rs1361962678
Type: single nucleotide variant
Location: chr20:63541521 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 349: 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-arg349gln (accessed [today's date]).

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