Is SRMS p.Lys307Asn (c.921G>C) pathogenic?

SRMS p.Lys307Asn (c.921G>C) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-19). AlphaMissense: ambiguous (0.4643); Very rare (popmax 0.00441%, nfe).

How common is SRMS p.Lys307Asn (c.921G>C) in the general population?

SRMS p.Lys307Asn (c.921G>C) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about SRMS p.Lys307Asn (c.921G>C)?

AlphaMissense predicts ambiguous (score 0.4643) — an in-silico prediction, not a clinical call.

SRMS p.Lys307Asn

c.921G>C · rs34412104 · VCV994345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4643	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	LLR -7.80	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.95	GERP -2.4, phastCons 0.004
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	17.34	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 0.00441% European (non-Finnish) · 52/1,178,504 alleles

Filtering AF 0.00343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00329% 53/1,610,844 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,664
Remaining individualsnot grpmax-eligible	0.0016%	62,328

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.Lys307Asn
Coding: c.921G>C
MANE Select: NM_080823
dbSNP: rs34412104
Type: single nucleotide variant
Location: chr20:63542188 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 307: 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-lys307asn (accessed [today's date]).

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