Is EVC2 p.Ser114Ter (c.341C>G) pathogenic?

EVC2 p.Ser114Ter (c.341C>G) is classified Pathogenic/Likely pathogenic in EVC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00667%, amr); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Ser114Ter (c.341C>G)?

EVC2 p.Ser114Ter (c.341C>G) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Ser114Ter (c.341C>G) in the general population?

EVC2 p.Ser114Ter (c.341C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

EVC2 p.Ser114Ter

c.341C>G · rs748820015 · VCV580714

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 22
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.5	GERP -3.2
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000558% 9/1,614,084 alleles · very rare exomes 7/1,461,884 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
African / African-American	0.004%	24,975
East Asian	0.00223%	44,892
European (non-Finnish)	8.47e-05%	1,180,038

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.Ser114Ter
Coding: c.341C>G
MANE Select: NM_147127
dbSNP: rs748820015
Type: single nucleotide variant
Location: chr4:5694444 (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

Ellis-van Creveld syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type

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-ser114ter (accessed [today's date]).

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