Is SRMS p.Arg147Trp (c.439C>T) pathogenic?

SRMS p.Arg147Trp (c.439C>T) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely benign (0.2498); Ultra-rare (popmax 0.0504%, sas).

How common is SRMS p.Arg147Trp (c.439C>T) in the general population?

SRMS p.Arg147Trp (c.439C>T) is ultra-rare (popmax 0.0504%, sas) (gnomAD).

What do computational predictors say about SRMS p.Arg147Trp (c.439C>T)?

AlphaMissense predicts likely benign (score 0.2498) — an in-silico prediction, not a clinical call.

SRMS p.Arg147Trp

c.439C>T · rs372015286 · VCV3170012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2498 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0504%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2498	likely benign
REVEL	0.708	pathogenic-leaning
SaProt	LLR -14.18	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 1.8	GERP -2.7, phastCons 0.96
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	23.1	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 0.0504% South Asian · 38/75,466 alleles

Filtering AF 0.0377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0332%

Overall 0.00494% 73/1,476,380 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0504%	1,986
Middle Eastern	0.0225%	4,454
Remaining individualsnot grpmax-eligible	0.00706%	14,166
African / African-American	0.00584%	17,121
European (non-Finnish)	0.00233%	42,860

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.Arg147Trp
Coding: c.439C>T
MANE Select: NM_080823
dbSNP: rs372015286
Type: single nucleotide variant
Location: chr20:63544266 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 147: the sh2 domain

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

Similar variants

SRMS p.Arg147Gln 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-arg147trp (accessed [today's date]).

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