Is SRMS p.Pro448Leu (c.1343C>T) pathogenic?

SRMS p.Pro448Leu (c.1343C>T) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-03). AlphaMissense: ambiguous (0.3573); Very rare (popmax 0.00941%, nfe).

How common is SRMS p.Pro448Leu (c.1343C>T) in the general population?

SRMS p.Pro448Leu (c.1343C>T) is very rare (popmax 0.00941%, nfe) (gnomAD).

What do computational predictors say about SRMS p.Pro448Leu (c.1343C>T)?

AlphaMissense predicts ambiguous (score 0.3573) — an in-silico prediction, not a clinical call.

SRMS p.Pro448Leu

c.1343C>T · rs373925989 · VCV2224192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00941%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3573	ambiguous
REVEL	0.612	indeterminate
SaProt	LLR -13.83	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	23.8	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 0.00941% European (non-Finnish) · 111/1,179,450 alleles

Filtering AF 0.00792% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.00865% 139/1,607,060 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0305%	3,282
European (non-Finnish)grpmax	0.00941%	10,626
Admixed American	0.00668%	14,980
African / African-American	0.00401%	24,960
South Asian	0.0022%	45,496

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro448Leu
Coding: c.1343C>T
MANE Select: NM_080823
dbSNP: rs373925989
Type: single nucleotide variant
Location: chr20:63540942 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 448: the protein kinase domain

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

Similar variants

SRMS p.Pro448Ala 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-pro448leu (accessed [today's date]).

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