Is EVC p.Lys445Gln (c.1333A>C) pathogenic?

EVC p.Lys445Gln (c.1333A>C) is classified Benign/Likely benign in EVC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-02). AlphaMissense: likely benign (0.1483); Low-frequency (popmax 1.79%, eas); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Lys445Gln (c.1333A>C)?

EVC p.Lys445Gln (c.1333A>C) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Lys445Gln (c.1333A>C) in the general population?

EVC p.Lys445Gln (c.1333A>C) is low-frequency (popmax 1.79%, eas) (gnomAD).

What do computational predictors say about EVC p.Lys445Gln (c.1333A>C)?

AlphaMissense predicts likely benign (score 0.1483) — an in-silico prediction, not a clinical call.

EVC p.Lys445Gln

c.1333A>C · rs116952023 · VCV349175

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1483 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.79%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.1483	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -4.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.3	GERP -0.68, phastCons 0.99
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	18.33	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 1.79% East Asian · 801/44,862 alleles

Filtering AF 1.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.64%

Overall 0.13% 2,095/1,614,162 alleles · low-frequency exomes 1,821/1,461,866 · genomes 274/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.79%	56
Finnishnot grpmax-eligible	0.654%	153
Remaining individualsnot grpmax-eligible	0.434%	231
South Asian	0.18%	555
Middle Eastern	0.0495%	2,019
European (non-Finnish)	0.0352%	2,843
Admixed American	0.0183%	5,457
African / African-American	0.0133%	7,506
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Lys445Gln
Coding: c.1333A>C
MANE Select: NM_153717
dbSNP: rs116952023
Type: single nucleotide variant
Location: chr4:5753802 (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 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
EVC c.2304+2T>C 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-lys445gln (accessed [today's date]).

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