Is EVC2 p.Thr748= (c.2244C>T) pathogenic?

EVC2 p.Thr748= (c.2244C>T) is classified Conflicting classifications of pathogenicity in EVC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-13). Rare (popmax 0.312%, afr); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Thr748= (c.2244C>T)?

EVC2 p.Thr748= (c.2244C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Thr748= (c.2244C>T) in the general population?

EVC2 p.Thr748= (c.2244C>T) is rare (popmax 0.312%, afr) (gnomAD).

EVC2 p.Thr748=

c.2244C>T · rs146588335 · VCV194443

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.312%, afr)

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -15	GERP -4.1
Overall
CADD	0.458	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.312% African / African-American · 234/74,972 alleles

Filtering AF 0.279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.267%

Overall 0.0252% 406/1,614,020 alleles · rare exomes 282/1,461,830 · genomes 124/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.312%	320
Remaining individualsnot grpmax-eligible	0.0272%	3,677
European (non-Finnish)	0.0122%	8,195
Admixed American	0.0117%	8,573
South Asian	0.00329%	30,355
East Asian	0.00223%	44,844

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.Thr748=
Coding: c.2244C>T
MANE Select: NM_147127
dbSNP: rs146588335
Type: single nucleotide variant
Location: chr4:5622794 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33

Full EVC2 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

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
EVC2 c.450+2T>C Likely pathogenic ★★ same condition
EVC2 c.451-2A>G 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-thr748 (accessed [today's date]).

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