Is EVC p.Leu148= (c.442T>C) pathogenic?

EVC p.Leu148= (c.442T>C) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-26). Ultra-rare (popmax 0.06%, amr); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Leu148= (c.442T>C)?

EVC p.Leu148= (c.442T>C) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC p.Leu148= (c.442T>C) in the general population?

EVC p.Leu148= (c.442T>C) is ultra-rare (popmax 0.06%, amr) (gnomAD).

EVC p.Leu148=

c.442T>C · rs139931919 · VCV349109

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.30	acceptor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.52	GERP -3.4
Overall
CADD	1.541	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.06% Admixed American · 36/59,962 alleles

Filtering AF 0.0445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.0322% 519/1,613,474 alleles · ultra-rare exomes 485/1,461,296 · genomes 34/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,666
European (non-Finnish)	0.0391%	2,559
Remaining individualsnot grpmax-eligible	0.0304%	3,287
African / African-American	0.00267%	37,499
South Asian	0.0011%	91,070

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: EVC
Protein: p.Leu148=
Coding: c.442T>C
MANE Select: NM_153717
dbSNP: rs139931919
Type: single nucleotide variant
Location: chr4:5731482 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

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

Disease context

Ellis-van Creveld syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type

Similar variants

EVC p.Leu148Ser Uncertain significance ★ same residue
EVC c.1098+1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.175-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-1G>A Pathogenic/Likely pathogenic ★★ same condition
EVC c.1777-2A>G Pathogenic/Likely pathogenic ★★ same condition
EVC c.1886+1G>C Likely pathogenic ★★ same condition
EVC c.1886+5G>A Pathogenic ★★ same condition
EVC c.1886+5G>T Pathogenic/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/evc-p-leu148 (accessed [today's date]).

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