Is EVC2 p.Arg449Trp (c.1345C>T) pathogenic?

EVC2 p.Arg449Trp (c.1345C>T) is classified Uncertain significance in EVC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-27). AlphaMissense: ambiguous (0.3531); Ultra-rare (popmax 0.0178%, eas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Arg449Trp (c.1345C>T)?

EVC2 p.Arg449Trp (c.1345C>T) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Arg449Trp (c.1345C>T) in the general population?

EVC2 p.Arg449Trp (c.1345C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about EVC2 p.Arg449Trp (c.1345C>T)?

AlphaMissense predicts ambiguous (score 0.3531) — an in-silico prediction, not a clinical call.

EVC2 p.Arg449Trp

c.1345C>T · rs778943940 · VCV2039223

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3531 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.3531	ambiguous
REVEL	0.517	indeterminate
SaProt	LLR -10.15	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 0.32, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	27.2	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 0.0178% East Asian · 8/44,878 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00459% 74/1,613,872 alleles · ultra-rare exomes 65/1,461,876 · genomes 9/151,996 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
South Asian	0.011%	9,107
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Admixed American	0.00667%	14,997
European (non-Finnish)	0.00373%	26,818
Finnishnot grpmax-eligible	0.00156%	63,998
African / African-American	0.00134%	74,842

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.Arg449Trp
Coding: c.1345C>T
MANE Select: NM_147127
dbSNP: rs778943940
Type: single nucleotide variant
Location: chr4:5640639 (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 p.Arg449Gln Uncertain significance ★★ ⚠ 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
EVC2 c.450+2T>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/evc2-p-arg449trp (accessed [today's date]).

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