Is EVC p.Pro30Leu (c.89C>T) pathogenic?

EVC p.Pro30Leu (c.89C>T) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-17). AlphaMissense: ambiguous (0.4538); Rare (popmax 0.244%, nfe); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Pro30Leu (c.89C>T)?

EVC p.Pro30Leu (c.89C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Pro30Leu (c.89C>T) in the general population?

EVC p.Pro30Leu (c.89C>T) is rare (popmax 0.244%, nfe) (gnomAD).

What do computational predictors say about EVC p.Pro30Leu (c.89C>T)?

AlphaMissense predicts ambiguous (score 0.4538) — an in-silico prediction, not a clinical call.

EVC p.Pro30Leu

c.89C>T · rs886044558 · VCV290794

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4538 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.244%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.4538	ambiguous
REVEL	0.052	moderately benign-leaning
SaProt	LLR -0.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.99	GERP 0.21, phastCons 0.14
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	20.6	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 0.244% European (non-Finnish) · 2,164/885,132 alleles

Filtering AF 0.236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.21% 2,241/1,066,526 alleles · rare exomes 2,088/918,554 · genomes 153/147,972 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.244%	409
Remaining individualsnot grpmax-eligible	0.117%	855
Finnishnot grpmax-eligible	0.0521%	1,918
African / African-American	0.0408%	2,449
Admixed American	0.0157%	6,374
South Asian	0.00426%	23,450

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.Pro30Leu
Coding: c.89C>T
MANE Select: NM_153717
dbSNP: rs886044558
Type: single nucleotide variant
Location: chr4:5711469 (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.Pro30= Likely benign ★ same residue
EVC p.Pro30Ala Uncertain significance ★ ⚠ same residue
EVC p.Pro30Thr 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-pro30leu (accessed [today's date]).

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