Is EMC2 p.Pro186Ser (c.556C>T) pathogenic?

EMC2 p.Pro186Ser (c.556C>T) is classified Uncertain significance in EMC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.9268); Very rare (popmax 0.000256%, nfe).

How common is EMC2 p.Pro186Ser (c.556C>T) in the general population?

EMC2 p.Pro186Ser (c.556C>T) is very rare (popmax 0.000256%, nfe) (gnomAD).

What do computational predictors say about EMC2 p.Pro186Ser (c.556C>T)?

AlphaMissense predicts likely pathogenic (score 0.9268) — an in-silico prediction, not a clinical call.

EMC2 p.Pro186Ser

c.556C>T · VCV3508154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9268 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9268	likely pathogenic
REVEL	0.667	pathogenic-leaning
SaProt	LLR -10.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 43 kb · p 0.67 · regional, not allelic
Overall
CADD	28.8	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 0.000256% European (non-Finnish) · 3/1,172,216 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000188% 3/1,599,834 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: EMC2
Protein: p.Pro186Ser
Coding: c.556C>T
MANE Select: NM_014673
Type: single nucleotide variant
Location: chr8:108475928 (GRCh38)
Gene constraint: LOEUF 1.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.40 · 11 PDB

Full EMC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC2 p.Ala271Thr Uncertain significance ★ ⚠ same type
EMC2 p.Arg273Gln Uncertain significance ★ ⚠ same type
EMC2 p.Asn167Ser Uncertain significance ★ ⚠ same type
EMC2 p.Asp111Gly Uncertain significance ★ ⚠ same type
EMC2 p.Asp287His Uncertain significance ★ ⚠ same type
EMC2 p.Gln134Glu Uncertain significance ★ ⚠ same type
EMC2 p.Gln293His Uncertain significance ★ ⚠ same type
EMC2 p.Glu286Lys 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/emc2-p-pro186ser (accessed [today's date]).

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