Is MCOLN2 p.Pro175Ser (c.523C>T) pathogenic?

MCOLN2 p.Pro175Ser (c.523C>T) is classified Uncertain significance in MCOLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.0107%, afr).

How common is MCOLN2 p.Pro175Ser (c.523C>T) in the general population?

MCOLN2 p.Pro175Ser (c.523C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about MCOLN2 p.Pro175Ser (c.523C>T)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

MCOLN2 p.Pro175Ser

c.523C>T · VCV3293726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -4.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.7	GERP 0.47, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 70 kb · p 0.024 · regional, not allelic
Overall
CADD	19.51	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 0.0107% African / African-American · 8/74,766 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000497% 8/1,611,082 alleles · ultra-rare exomes 3/1,458,894 · genomes 5/152,188 · joint denominator

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: MCOLN2
Protein: p.Pro175Ser
Coding: c.523C>T
MANE Select: NM_153259
Type: single nucleotide variant
Location: chr1:84956473 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 8 PDB

Full MCOLN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCOLN2 c.1110+10G>A Benign ★★ same type
MCOLN2 c.1213-10T>A Benign ★★ same type
MCOLN2 p.Glu15= Benign ★★ same type
MCOLN2 p.Lys370Gln Benign ★★ same type
MCOLN2 p.Met365Val Benign ★★ same type
MCOLN2 p.Val20Ile Benign ★★ same type
MCOLN2 p.Ala127Ser Uncertain significance ★ ⚠ same type
MCOLN2 p.Ala134Gly 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/mcoln2-p-pro175ser (accessed [today's date]).

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