Is EVC p.Pro137Leu (c.410C>T) pathogenic?

EVC p.Pro137Leu (c.410C>T) is classified Uncertain significance in EVC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-17). AlphaMissense: likely pathogenic (0.7346); Very rare (popmax 0.00446%, eas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Pro137Leu (c.410C>T)?

EVC p.Pro137Leu (c.410C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC p.Pro137Leu (c.410C>T) in the general population?

EVC p.Pro137Leu (c.410C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about EVC p.Pro137Leu (c.410C>T)?

AlphaMissense predicts likely pathogenic (score 0.7346) — an in-silico prediction, not a clinical call.

EVC p.Pro137Leu

c.410C>T · rs2474667581 · VCV1947307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.7346	likely pathogenic · top 4% in EVC
REVEL	0.585	indeterminate
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,613,500 alleles · very rare exomes 6/1,461,448 · genomes 0/152,052 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
European (non-Finnish)	0.000339%	294,987

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.Pro137Leu
Coding: c.410C>T
MANE Select: NM_153717
dbSNP: rs2474667581
Type: single nucleotide variant
Location: chr4:5731450 (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.Pro137Thr Uncertain significance ★★ ⚠ same residue
EVC p.Pro137= Likely benign ★★ 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-pro137leu (accessed [today's date]).

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