Is EMX1 p.Pro8Ser (c.22C>T) pathogenic?

EMX1 p.Pro8Ser (c.22C>T) is classified Uncertain significance in EMX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). Very rare (popmax 0.000178%, nfe).

How common is EMX1 p.Pro8Ser (c.22C>T) in the general population?

EMX1 p.Pro8Ser (c.22C>T) is very rare (popmax 0.000178%, nfe) (gnomAD).

EMX1 p.Pro8Ser

c.22C>T · rs1309584484 · VCV2600837

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000178%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.111	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.29, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 6,504 bp · p 0.035 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000178% European (non-Finnish) · 2/1,121,174 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000542% 8/1,476,442 alleles · very rare exomes 6/1,324,638 · genomes 2/151,804 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0138%	7,225
European (non-Finnish)grpmax	0.000178%	560,588

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EMX1
Protein: p.Pro8Ser
Coding: c.22C>T
MANE Select: NM_004097
dbSNP: rs1309584484
Type: single nucleotide variant
Location: chr2:72917874 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.07

Full EMX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EMX1 p.Ala127Thr Uncertain significance ★ same type
EMX1 p.Ala150Thr Uncertain significance ★ same type
EMX1 p.Ala22Val Uncertain significance ★ same type
EMX1 p.Ala28Pro Uncertain significance ★ same type
EMX1 p.Ala28Val Uncertain significance ★ same type
EMX1 p.Ala31Thr Uncertain significance ★ same type
EMX1 p.Ala38Ser Uncertain significance ★ same type
EMX1 p.Ala39Thr 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/emx1-p-pro8ser (accessed [today's date]).

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