Is EVC p.Ala450Val (c.1349C>T) pathogenic?

EVC p.Ala450Val (c.1349C>T) is classified Conflicting classifications of pathogenicity in EVC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.1068); Very rare (popmax 0.00737%, nfe); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Ala450Val (c.1349C>T)?

EVC p.Ala450Val (c.1349C>T) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Ala450Val (c.1349C>T) in the general population?

EVC p.Ala450Val (c.1349C>T) is very rare (popmax 0.00737%, nfe) (gnomAD).

What do computational predictors say about EVC p.Ala450Val (c.1349C>T)?

AlphaMissense predicts likely benign (score 0.1068) — an in-silico prediction, not a clinical call.

EVC p.Ala450Val

c.1349C>T · rs749008952 · VCV287369

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00737%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.1068	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -1	GERP -0.63
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	11.58	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 0.00737% European (non-Finnish) · 87/1,180,012 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.00576% 93/1,614,002 alleles · very rare exomes 89/1,461,824 · genomes 4/152,178 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00737%	13,563
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00333%	30,002
Remaining individualsnot grpmax-eligible	0.0032%	31,241
African / African-American	0.00133%	74,926

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.Ala450Val
Coding: c.1349C>T
MANE Select: NM_153717
dbSNP: rs749008952
Type: single nucleotide variant
Location: chr4:5753818 (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

acrofacial dysostosis, Weyers type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ellis-van Creveld syndrome

Similar variants

EVC p.Ala450= 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-ala450val (accessed [today's date]).

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