Is EVC p.Ala114Val (c.341C>T) pathogenic?

EVC p.Ala114Val (c.341C>T) is classified Benign/Likely benign in EVC (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-05-09). AlphaMissense: likely pathogenic (0.7157); Common (popmax 18.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC p.Ala114Val (c.341C>T)?

EVC p.Ala114Val (c.341C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

What do computational predictors say about EVC p.Ala114Val (c.341C>T)?

AlphaMissense predicts likely pathogenic (score 0.7157) — an in-silico prediction, not a clinical call.

EVC p.Ala114Val

Q: How common is EVC p.Ala114Val (c.341C>T) in the general population?

EVC p.Ala114Val (c.341C>T) is common (popmax 18.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.341C>T · rs16837598 · VCV262779

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7157 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.7157	likely pathogenic · top 5% in EVC
REVEL	0.377	indeterminate
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	24.6	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 18.5% African / African-American · 13,851/74,938 alleles

Filtering AF 18.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.1%

Overall 1.46% 23,594/1,614,036 alleles · common exomes 15,090/1,461,878 · genomes 8,504/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	18.5%	5
Amishnot grpmax-eligible	9.12%	11
South Asian	2.86%	35
Middle Eastern	2.64%	38
Remaining individualsnot grpmax-eligible	1.83%	55
Admixed American	1.44%	69
Ashkenazi Jewishnot grpmax-eligible	1.09%	92
European (non-Finnish)	0.384%	261
Finnishnot grpmax-eligible	0.0422%	2,371
East Asian	0.0156%	6,411

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.Ala114Val
Coding: c.341C>T
MANE Select: NM_153717
dbSNP: rs16837598
Type: single nucleotide variant
Location: chr4:5729347 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49
Residue 114: a UniProt-annotated variant site (in)

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.Ala114Thr Uncertain significance ★★ ⚠ same residue
EVC p.Ala114fs Pathogenic ★ same residue
EVC p.Ala114Ser 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

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-ala114val (accessed [today's date]).

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