Is EMC8 p.Pro165Leu (c.494C>T) pathogenic?

EMC8 p.Pro165Leu (c.494C>T) is classified Uncertain significance in EMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely benign (0.0639); Ultra-rare (popmax 0.0329%, mid).

How common is EMC8 p.Pro165Leu (c.494C>T) in the general population?

EMC8 p.Pro165Leu (c.494C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about EMC8 p.Pro165Leu (c.494C>T)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

EMC8 p.Pro165Leu

c.494C>T · rs141023992 · VCV2487877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0639 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0639	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -7.17	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 8.6	GERP -2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 20 kb · p 0.73 · regional, not allelic
Overall
CADD	21.2	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 0.0329% Middle Eastern · 2/6,070 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00105% 17/1,613,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,035
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00119%	84,285

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: EMC8
Protein: p.Pro165Leu
Coding: c.494C>T
MANE Select: NM_006067
dbSNP: rs141023992
Type: single nucleotide variant
Location: chr16:85779847 (GRCh38)
Gene constraint: LOEUF 0.915 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 91.60 · 9 PDB
Residue 165: an α-helix

Full EMC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMC8 p.Ala25Val Uncertain significance ★ ⚠ same type
EMC8 p.Ala32Val Uncertain significance ★ ⚠ same type
EMC8 p.Asp84Val Uncertain significance ★ ⚠ same type
EMC8 p.Glu181Lys Uncertain significance ★ ⚠ same type
EMC8 p.Gly3Trp Uncertain significance ★ ⚠ same type
EMC8 p.His85Arg Uncertain significance ★ ⚠ same type
EMC8 p.Ile125Val Uncertain significance ★ ⚠ same type
EMC8 p.Leu29Pro 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/emc8-p-pro165leu (accessed [today's date]).

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