Is EVC p.Ala565fs (c.1694del) pathogenic?

EVC p.Ala565fs (c.1694del) is classified Pathogenic in EVC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-09). Ultra-rare (popmax 0.0164%, mid); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Ala565fs (c.1694del)?

EVC p.Ala565fs (c.1694del) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Ala565fs (c.1694del) in the general population?

EVC p.Ala565fs (c.1694del) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

EVC p.Ala565fs

c.1694del · rs753014919 · VCV551227

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 21
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.19	GERP -3.4
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00533% 86/1,613,890 alleles · ultra-rare exomes 69/1,461,726 · genomes 17/152,164 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0391%	2,561
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00492%	20,344
Remaining individualsnot grpmax-eligible	0.0032%	31,239

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: EVC
Protein: p.Ala565fs
Coding: c.1694del
MANE Select: NM_153717
dbSNP: rs753014919
Type: Deletion
Location: chr4:5783682 (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

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

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC p.Ala565Thr Uncertain significance ★★ ⚠ same residue
EVC c.1783_1886+40del Pathogenic ★★ same condition
EVC c.1887-5_1904del Pathogenic/Likely pathogenic ★★ same condition
EVC c.2782+1del Pathogenic ★★ same condition
EVC p.Asn68fs Pathogenic ★★ same condition
EVC p.Asp132fs Pathogenic/Likely pathogenic ★★ same condition
EVC p.Gln424fs Pathogenic/Likely pathogenic ★★ same condition
EVC p.Gln584fs 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-ala565fs (accessed [today's date]).

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