Is SRMS p.Arg284Trp (c.850C>T) pathogenic?

SRMS p.Arg284Trp (c.850C>T) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1662); Very rare (popmax 0.00439%, sas).

How common is SRMS p.Arg284Trp (c.850C>T) in the general population?

SRMS p.Arg284Trp (c.850C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about SRMS p.Arg284Trp (c.850C>T)?

AlphaMissense predicts likely benign (score 0.1662) — an in-silico prediction, not a clinical call.

SRMS p.Arg284Trp

c.850C>T · rs750000755 · VCV2357968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1662	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -14.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP -1, phastCons 0.32
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	25.2	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 0.00439% South Asian · 4/91,084 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00136% 22/1,612,498 alleles · very rare exomes 20/1,460,256 · genomes 2/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,771
East Asian	0.00223%	44,876
Admixed American	0.00167%	59,986
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)	0.00127%	78,648

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.Arg284Trp
Coding: c.850C>T
MANE Select: NM_080823
dbSNP: rs750000755
Type: single nucleotide variant
Location: chr20:63542259 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 284: the protein kinase domain

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

Similar variants

SRMS p.Arg284Pro Uncertain significance ★ ⚠ same residue
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

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-arg284trp (accessed [today's date]).

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