Is MLC1 p.Ser280Pro (c.838T>C) pathogenic?

MLC1 p.Ser280Pro (c.838T>C) is classified Uncertain significance in MLC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-13). AlphaMissense: likely pathogenic (0.8318); Absent from gnomAD v4.1.

How common is MLC1 p.Ser280Pro (c.838T>C) in the general population?

MLC1 p.Ser280Pro (c.838T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MLC1 p.Ser280Pro (c.838T>C)?

AlphaMissense predicts likely pathogenic (score 0.8318) — an in-silico prediction, not a clinical call.

MLC1 p.Ser280Pro

c.838T>C · rs2518488167 · VCV1998382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8318 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8318	likely pathogenic
REVEL	0.74	pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.5	GERP 0.23, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 23 kb · p 0.13 · regional, not allelic
Overall
CADD	24.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MLC1
Protein: p.Ser280Pro
Coding: c.838T>C
MANE Select: NM_015166
dbSNP: rs2518488167
Type: single nucleotide variant
Location: chr22:50068489 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.29
Residue 280: a UniProt-annotated variant site (in mlc1; accumulates in the cytoplasmic perinuclear region and endoplasmic reticulum; affects the interaction with atp1b1, trpv4, aqp4 and hepacam)

Full MLC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MLC1 p.Ser280Ter Likely pathogenic ★ same residue
MLC1 p.Ser280Leu Conflicting classifications of pathogenicity ⚠ same residue
MLC1 p.Ser280_Phe281delinsIleLeu Uncertain significance same residue
MLC1 c.1059+1G>A Likely pathogenic ★★ same type
MLC1 c.321+1G>A Likely pathogenic ★★ same type
MLC1 c.321+2T>C Likely pathogenic ★★ same type
MLC1 c.321+2T>G Likely pathogenic ★★ same type
MLC1 c.423+1G>A Pathogenic/Likely pathogenic ★★ 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/mlc1-p-ser280pro (accessed [today's date]).

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