Is EVC p.Thr347= (c.1041G>A) pathogenic?

EVC p.Thr347= (c.1041G>A) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-11). Ultra-rare (popmax 0.06%, amr); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Thr347= (c.1041G>A)?

EVC p.Thr347= (c.1041G>A) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC p.Thr347= (c.1041G>A) in the general population?

EVC p.Thr347= (c.1041G>A) is ultra-rare (popmax 0.06%, amr) (gnomAD).

EVC p.Thr347=

c.1041G>A · rs148418233 · VCV498733

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.06%, amr)

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -3.9
Overall
CADD	1.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.06% Admixed American · 36/60,022 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0392%

Overall 0.0115% 186/1,614,124 alleles · ultra-rare exomes 177/1,461,880 · genomes 9/152,244 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.06%	1,667
Middle Eastern	0.0165%	6,062
South Asian	0.0165%	6,072
European (non-Finnish)	0.0105%	9,516
East Asian	0.00891%	11,219
African / African-American	0.00533%	18,755
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Thr347=
Coding: c.1041G>A
MANE Select: NM_153717
dbSNP: rs148418233
Type: single nucleotide variant
Location: chr4:5748249 (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.Thr347Met Likely benign ★★ 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-thr347 (accessed [today's date]).

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