Is EVC p.Ser158Cys (c.473C>G) pathogenic?

EVC p.Ser158Cys (c.473C>G) is classified Benign/Likely benign in EVC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0772); Low-frequency (popmax 3.06%, sas); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC p.Ser158Cys (c.473C>G)?

EVC p.Ser158Cys (c.473C>G) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC p.Ser158Cys (c.473C>G) in the general population?

EVC p.Ser158Cys (c.473C>G) is low-frequency (popmax 3.06%, sas) (gnomAD).

What do computational predictors say about EVC p.Ser158Cys (c.473C>G)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

EVC p.Ser158Cys

c.473C>G · rs150284356 · VCV197382

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.06%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -8.33	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 1.1	GERP 0.52, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	17.75	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 3.06% South Asian · 2,788/91,074 alleles

Filtering AF 2.97% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.93%

Overall 0.185% 2,988/1,614,126 alleles · low-frequency exomes 2,844/1,461,890 · genomes 144/152,236 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	3.06%	33
Remaining individualsnot grpmax-eligible	0.181%	553
Middle Eastern	0.0825%	1,212
African / African-American	0.0173%	5,772
European (non-Finnish)	0.00551%	18,154
Admixed American	0.00333%	30,006
East Asian	0.00223%	44,860
Finnishnot grpmax-eligible	0.00156%	64,030

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.Ser158Cys
Coding: c.473C>G
MANE Select: NM_153717
dbSNP: rs150284356
Type: single nucleotide variant
Location: chr4:5731513 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49
Residue 158: the 'disordered' region

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.Ser158= 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-ser158cys (accessed [today's date]).

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