Is EVC2 p.Arg608His (c.1823G>A) pathogenic?

EVC2 p.Arg608His (c.1823G>A) is classified Conflicting classifications of pathogenicity in EVC2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-06-03). AlphaMissense: likely benign (0.0902); Rare (popmax 0.19%, nfe); Associated with acrofacial dysostosis, Weyers type.

What condition is associated with EVC2 p.Arg608His (c.1823G>A)?

EVC2 p.Arg608His (c.1823G>A) is associated with acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome, Beemer-Langer syndrome (ClinVar).

How common is EVC2 p.Arg608His (c.1823G>A) in the general population?

EVC2 p.Arg608His (c.1823G>A) is rare (popmax 0.19%, nfe) (gnomAD).

What do computational predictors say about EVC2 p.Arg608His (c.1823G>A)?

AlphaMissense predicts likely benign (score 0.0902) — an in-silico prediction, not a clinical call.

EVC2 p.Arg608His

c.1823G>A · rs145693546 · VCV281122

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0902 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.19%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acrofacial dysostosis, Weyers type

Computational evidence

Protein change
AlphaMissense	0.0902	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -7.73	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 2	GERP 0.69, phastCons 0.96
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	19.37	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 0.19% European (non-Finnish) · 2,237/1,179,980 alleles

Filtering AF 0.183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.18%

Overall 0.174% 2,808/1,613,972 alleles · rare exomes 2,618/1,461,868 · genomes 190/152,104 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.27%	79
European (non-Finnish)grpmax	0.19%	527
Remaining individualsnot grpmax-eligible	0.15%	665
Admixed American	0.0867%	1,154
Finnishnot grpmax-eligible	0.0359%	2,783
African / African-American	0.0187%	5,355
Middle Eastern	0.0165%	6,058
South Asian	0.0121%	8,280
East Asian	0.00223%	44,862

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.Arg608His
Coding: c.1823G>A
MANE Select: NM_147127
dbSNP: rs145693546
Type: single nucleotide variant
Location: chr4:5628622 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 73.33

Full EVC2 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 Beemer-Langer syndrome

Similar variants

EVC2 p.Arg608Cys Uncertain significance ★★ ⚠ 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
EVC2 c.450+2T>C 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-arg608his (accessed [today's date]).

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