Is EMC1 p.Pro886Ser (c.2656C>T) pathogenic?

EMC1 p.Pro886Ser (c.2656C>T) is classified Uncertain significance in EMC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.3277); Ultra-rare (popmax 0.0184%, amr).

How common is EMC1 p.Pro886Ser (c.2656C>T) in the general population?

EMC1 p.Pro886Ser (c.2656C>T) is ultra-rare (popmax 0.0184%, amr) (gnomAD).

What do computational predictors say about EMC1 p.Pro886Ser (c.2656C>T)?

AlphaMissense predicts likely benign (score 0.3277) — an in-silico prediction, not a clinical call.

EMC1 p.Pro886Ser

c.2656C>T · rs755986625 · VCV856504

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0184%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3277	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -8.88	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 4e-06 · regional, not allelic
Overall
CADD	28.1	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 0.0184% Admixed American · 11/59,940 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.00136% 22/1,613,434 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0184%	5,449
Middle Eastern	0.0164%	6,084
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,398
Remaining individualsnot grpmax-eligible	0.0032%	31,234
African / African-American	0.00134%	74,748
European (non-Finnish)	0.000254%	393,272

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: EMC1
Protein: p.Pro886Ser
Coding: c.2656C>T
MANE Select: NM_015047
dbSNP: rs755986625
Type: single nucleotide variant
Location: chr1:19220780 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.67 · 10 PDB

Full EMC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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EMC1 p.Arg660Ter Pathogenic/Likely pathogenic ★★ same type
EMC1 p.Arg687Ter Pathogenic/Likely pathogenic ★★ same type
EMC1 p.Arg69Ter Pathogenic/Likely pathogenic ★★ same type
EMC1 p.Arg908Ter Pathogenic ★★ same type
EMC1 p.Leu266Ter 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/emc1-p-pro886ser (accessed [today's date]).

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