Is SRMS p.Arg444Trp (c.1330C>T) pathogenic?

SRMS p.Arg444Trp (c.1330C>T) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.2751); Ultra-rare (popmax 0.033%, mid).

How common is SRMS p.Arg444Trp (c.1330C>T) in the general population?

SRMS p.Arg444Trp (c.1330C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about SRMS p.Arg444Trp (c.1330C>T)?

AlphaMissense predicts likely benign (score 0.2751) — an in-silico prediction, not a clinical call.

SRMS p.Arg444Trp

c.1330C>T · rs546690881 · VCV3170009

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2751 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2751	likely benign
REVEL	0.698	pathogenic-leaning
SaProt	LLR -14.73	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	21.3	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 0.033% Middle Eastern · 2/6,056 alleles

Filtering AF 0.00677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00243% 39/1,608,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,028
South Asian	0.0121%	8,273
East Asian	0.00892%	11,212
Remaining individualsnot grpmax-eligible	0.00801%	12,484
African / African-American	0.008%	12,503
Finnishnot grpmax-eligible	0.00511%	19,580
European (non-Finnish)	0.000678%	147,441

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.Arg444Trp
Coding: c.1330C>T
MANE Select: NM_080823
dbSNP: rs546690881
Type: single nucleotide variant
Location: chr20:63540955 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 444: the protein kinase domain

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

Similar variants

SRMS p.Arg444Gln 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-arg444trp (accessed [today's date]).

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