Is EVC p.Pro157Ala (c.469C>G) pathogenic?

EVC p.Pro157Ala (c.469C>G) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-05-22). AlphaMissense: likely benign (0.0995); Rare (popmax 0.841%, mid); Associated with Inborn genetic diseases.

What condition is associated with EVC p.Pro157Ala (c.469C>G)?

EVC p.Pro157Ala (c.469C>G) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Pro157Ala (c.469C>G) in the general population?

EVC p.Pro157Ala (c.469C>G) is rare (popmax 0.841%, mid) (gnomAD).

What do computational predictors say about EVC p.Pro157Ala (c.469C>G)?

AlphaMissense predicts likely benign (score 0.0995) — an in-silico prediction, not a clinical call.

EVC p.Pro157Ala

c.469C>G · rs146729456 · VCV197384

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0995 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.841%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0995	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	21.5	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 0.841% Middle Eastern · 51/6,062 alleles

Filtering AF 0.806% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.801%

Overall 0.688% 11,104/1,614,130 alleles · rare exomes 10,424/1,461,892 · genomes 680/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.841%	119
European (non-Finnish)	0.82%	122
Ashkenazi Jewishnot grpmax-eligible	0.719%	139
Remaining individualsnot grpmax-eligible	0.597%	168
Finnishnot grpmax-eligible	0.5%	200
Admixed American	0.492%	203
African / African-American	0.136%	736
South Asian	0.0813%	1,231

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.Pro157Ala
Coding: c.469C>G
MANE Select: NM_153717
dbSNP: rs146729456
Type: single nucleotide variant
Location: chr4:5731509 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49
Residue 157: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type Ellis-van Creveld syndrome

Similar variants

EVC p.Pro157Leu 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-pro157ala (accessed [today's date]).

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