Is SRMS p.Arg147Gln (c.440G>A) pathogenic?

SRMS p.Arg147Gln (c.440G>A) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.2595); Ultra-rare (popmax 0.0324%, amr).

How common is SRMS p.Arg147Gln (c.440G>A) in the general population?

SRMS p.Arg147Gln (c.440G>A) is ultra-rare (popmax 0.0324%, amr) (gnomAD).

What do computational predictors say about SRMS p.Arg147Gln (c.440G>A)?

AlphaMissense predicts likely benign (score 0.2595) — an in-silico prediction, not a clinical call.

SRMS p.Arg147Gln

c.440G>A · VCV3449359

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2595 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0324%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2595	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -14.39	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 2.7	GERP 1.4, phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	23.7	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 0.0324% Admixed American · 12/37,078 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00495% 73/1,475,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0324%	3,090
Remaining individualsnot grpmax-eligible	0.0106%	9,439
South Asian	0.00531%	18,848
African / African-American	0.00438%	22,826
European (non-Finnish)	0.00413%	24,215
Ashkenazi Jewishnot grpmax-eligible	0.00383%	26,134
East Asian	0.00286%	34,922

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.Arg147Gln
Coding: c.440G>A
MANE Select: NM_080823
Type: single nucleotide variant
Location: chr20:63544265 (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.Arg147Trp 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-arg147gln (accessed [today's date]).

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