Is EVC2 p.Ser6= (c.18C>T) pathogenic?

EVC2 p.Ser6= (c.18C>T) is classified Conflicting classifications of pathogenicity in EVC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-05-12). Rare (popmax 0.689%, afr); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Ser6= (c.18C>T)?

EVC2 p.Ser6= (c.18C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Ser6= (c.18C>T) in the general population?

EVC2 p.Ser6= (c.18C>T) is rare (popmax 0.689%, afr) (gnomAD).

EVC2 p.Ser6=

c.18C>T · rs556910528 · VCV193502

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.689%, afr)

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.74	GERP -2.1, phastCons 0.001
Overall
CADD	5.711	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.689% African / African-American · 470/68,240 alleles

Filtering AF 0.637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.617%

Overall 0.0362% 536/1,479,506 alleles · rare exomes 246/1,327,282 · genomes 290/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.689%	145
Admixed American	0.0766%	1,306
Remaining individualsnot grpmax-eligible	0.0402%	2,491
Middle Eastern	0.0237%	4,222
South Asian	0.00129%	77,630
European (non-Finnish)	0.000712%	140,357

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: EVC2
Protein: p.Ser6=
Coding: c.18C>T
MANE Select: NM_147127
dbSNP: rs556910528
Type: single nucleotide variant
Location: chr4:5708496 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33

Full EVC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acrofacial dysostosis, Weyers type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC2 c.2046+1G>A Likely pathogenic ★★ same condition
EVC2 c.2047-2A>G Likely pathogenic ★★ same condition
EVC2 c.229-1G>T Likely pathogenic ★★ same condition
EVC2 c.229-2A>G Likely pathogenic ★★ same condition
EVC2 c.3360+1G>A Pathogenic ★★ same condition
EVC2 c.3659+2T>C Pathogenic/Likely pathogenic ★★ same condition
EVC2 c.450+2T>C Likely pathogenic ★★ same condition
EVC2 c.451-2A>G Likely pathogenic ★★ same condition

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/evc2-p-ser6 (accessed [today's date]).

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