Is EVC2 p.Asp799His (c.2395G>C) pathogenic?

EVC2 p.Asp799His (c.2395G>C) is classified Benign/Likely benign in EVC2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1467); Low-frequency (popmax 1.08%, eas); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Asp799His (c.2395G>C)?

EVC2 p.Asp799His (c.2395G>C) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Asp799His (c.2395G>C) in the general population?

EVC2 p.Asp799His (c.2395G>C) is low-frequency (popmax 1.08%, eas) (gnomAD).

What do computational predictors say about EVC2 p.Asp799His (c.2395G>C)?

AlphaMissense predicts likely benign (score 0.1467) — an in-silico prediction, not a clinical call.

EVC2 p.Asp799His

c.2395G>C · rs143491078 · VCV349057

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1467 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.08%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.1467	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -4.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP 0.99, phastCons 0.003
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	17.28	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 1.08% East Asian · 486/44,848 alleles

Filtering AF 1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.973%

Overall 0.0994% 1,605/1,614,074 alleles · low-frequency exomes 1,348/1,461,880 · genomes 257/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.08%	92
Admixed American	0.967%	103
Remaining individualsnot grpmax-eligible	0.166%	601
Finnishnot grpmax-eligible	0.137%	728
South Asian	0.113%	884
Middle Eastern	0.066%	1,516
Ashkenazi Jewishnot grpmax-eligible	0.0574%	1,741
African / African-American	0.0453%	2,207
European (non-Finnish)	0.016%	6,243

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.Asp799His
Coding: c.2395G>C
MANE Select: NM_147127
dbSNP: rs143491078
Type: single nucleotide variant
Location: chr4:5622643 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33
Residue 799: the 'disordered' region

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.Asp799= Likely benign ★ same residue
EVC2 p.Asp799fs Likely pathogenic ★ 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

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-asp799his (accessed [today's date]).

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