Is EVC2 p.Pro47Thr (c.139C>A) pathogenic?

EVC2 p.Pro47Thr (c.139C>A) is classified Uncertain significance in EVC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.0946); Ultra-rare (popmax 0.0218%, eas); Associated with Inborn genetic diseases.

What condition is associated with EVC2 p.Pro47Thr (c.139C>A)?

EVC2 p.Pro47Thr (c.139C>A) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Pro47Thr (c.139C>A) in the general population?

EVC2 p.Pro47Thr (c.139C>A) is ultra-rare (popmax 0.0218%, eas) (gnomAD).

What do computational predictors say about EVC2 p.Pro47Thr (c.139C>A)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

EVC2 p.Pro47Thr

c.139C>A · rs376923652 · VCV2040565

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.091	GERP 0.89
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	15.18	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0218% East Asian · 8/36,740 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00782%

Overall 0.000603% 9/1,493,142 alleles · ultra-rare exomes 7/1,341,112 · genomes 2/152,030 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0218%	4,593
European (non-Finnish)	8.86e-05%	1,128,526

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: EVC2
Protein: p.Pro47Thr
Coding: c.139C>A
MANE Select: NM_147127
dbSNP: rs376923652
Type: single nucleotide variant
Location: chr4:5708375 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33
Residue 47: the 'disordered' region

Full EVC2 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

EVC2 p.Pro47Ser Uncertain significance ★ ⚠ same residue
EVC2 p.Pro47= Likely benign ★ same residue
EVC2 c.2046+1G>A Likely pathogenic ★★ same condition
EVC2 c.2047-2A>G Likely pathogenic ★★ same condition
EVC2 c.229-1G>T Likely pathogenic ★★ same condition
EVC2 c.229-2A>G Likely pathogenic ★★ same condition
EVC2 c.3360+1G>A Pathogenic ★★ same condition
EVC2 c.3659+2T>C 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/evc2-p-pro47thr (accessed [today's date]).

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