Is EVC p.Pro137= (c.411G>A) pathogenic?

EVC p.Pro137= (c.411G>A) is classified Likely benign in EVC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0111%, eas); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Pro137= (c.411G>A)?

EVC p.Pro137= (c.411G>A) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Pro137= (c.411G>A) in the general population?

EVC p.Pro137= (c.411G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

EVC p.Pro137=

c.411G>A · rs758770136 · VCV1134742

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

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 -13	GERP -3.4
Overall
CADD	0.126	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% East Asian · 5/44,888 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00285% 46/1,613,228 alleles · ultra-rare exomes 43/1,461,456 · genomes 3/151,772 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,978
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
European (non-Finnish)	0.00314%	31,890
Admixed American	0.00167%	59,946
Remaining individualsnot grpmax-eligible	0.0016%	62,434
South Asian	0.0011%	91,044

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.Pro137=
Coding: c.411G>A
MANE Select: NM_153717
dbSNP: rs758770136
Type: single nucleotide variant
Location: chr4:5731451 (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.Pro137Thr Uncertain significance ★★ ⚠ same residue
EVC p.Pro137Leu Uncertain significance ★ ⚠ same residue
EVC p.Pro137Ser 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

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-pro137 (accessed [today's date]).

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