Is SRMS p.Pro389Leu (c.1166C>T) pathogenic?

SRMS p.Pro389Leu (c.1166C>T) is classified Uncertain significance in SRMS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.625); Very rare (popmax 0.00414%, afr).

How common is SRMS p.Pro389Leu (c.1166C>T) in the general population?

SRMS p.Pro389Leu (c.1166C>T) is very rare (popmax 0.00414%, afr) (gnomAD).

What do computational predictors say about SRMS p.Pro389Leu (c.1166C>T)?

AlphaMissense predicts likely pathogenic (score 0.625) — an in-silico prediction, not a clinical call.

SRMS p.Pro389Leu

c.1166C>T · VCV3961992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.625 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00414%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.625	likely pathogenic
REVEL	0.523	indeterminate
SaProt	LLR -13.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,642 bp · p 0.4 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00414% African / African-American · 3/72,400 alleles

Filtering AF 0.0011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000505%

Overall 0.0011% 17/1,547,912 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00414%	24,133
South Asian	0.00122%	81,772
European (non-Finnish)	0.00113%	88,405

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.Pro389Leu
Coding: c.1166C>T
MANE Select: NM_080823
Type: single nucleotide variant
Location: chr20:63541310 (GRCh38)
Gene constraint: LOEUF 1.445 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.99
Residue 389: 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-pro389leu (accessed [today's date]).

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