Is EVC2 p.Ser74Asn (c.221G>A) pathogenic?

EVC2 p.Ser74Asn (c.221G>A) is classified Uncertain significance in EVC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-15). AlphaMissense: likely benign (0.1087); Very rare (popmax 0.00599%, nfe); Associated with Ellis-van Creveld syndrome.

What condition is associated with EVC2 p.Ser74Asn (c.221G>A)?

EVC2 p.Ser74Asn (c.221G>A) is associated with Ellis-van Creveld syndrome, acrofacial dysostosis, Weyers type (ClinVar).

How common is EVC2 p.Ser74Asn (c.221G>A) in the general population?

EVC2 p.Ser74Asn (c.221G>A) is very rare (popmax 0.00599%, nfe) (gnomAD).

What do computational predictors say about EVC2 p.Ser74Asn (c.221G>A)?

AlphaMissense predicts likely benign (score 0.1087) — an in-silico prediction, not a clinical call.

EVC2 p.Ser74Asn

c.221G>A · rs1191013607 · VCV546204

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00599%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ellis-van Creveld syndrome

Computational evidence

Protein change
AlphaMissense	0.1087	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -8.07	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 -0.069	GERP -2.3
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	3.976	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00599% European (non-Finnish) · 67/1,118,366 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0044%

Overall 0.00522% 77/1,476,196 alleles · very rare exomes 73/1,323,996 · genomes 4/152,200 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0191%	5,232
European (non-Finnish)grpmax	0.00599%	16,692
Remaining individualsnot grpmax-eligible	0.0035%	28,598
African / African-American	0.00293%	34,184
Admixed American	0.00231%	43,302

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser74Asn
Coding: c.221G>A
MANE Select: NM_147127
dbSNP: rs1191013607
Type: single nucleotide variant
Location: chr4:5708293 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33
Residue 74: 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 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
EVC2 c.451-2A>G 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-ser74asn (accessed [today's date]).

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