Is SRMS p.Leu153Phe (c.457C>T) pathogenic?

SRMS p.Leu153Phe (c.457C>T) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely benign (0.0856); Very rare (popmax 9e-05%, nfe).

How common is SRMS p.Leu153Phe (c.457C>T) in the general population?

SRMS p.Leu153Phe (c.457C>T) is very rare (popmax 9e-05%, nfe) (gnomAD).

What do computational predictors say about SRMS p.Leu153Phe (c.457C>T)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

SRMS p.Leu153Phe

c.457C>T · rs2082719103 · VCV2527029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -2.4, phastCons 0.82
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	11.74	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9e-05% European (non-Finnish) · 1/1,111,348 alleles

Overall 7.58e-05% 1/1,318,948 alleles · very rare

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.Leu153Phe
Coding: c.457C>T
MANE Select: NM_080823
dbSNP: rs2082719103
Type: single nucleotide variant
Location: chr20:63544248 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 153: the sh2 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-leu153phe (accessed [today's date]).

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