Is EVC2 p.Phe140Leu (c.418T>C) pathogenic?

EVC2 p.Phe140Leu (c.418T>C) is classified Uncertain significance in EVC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-11). AlphaMissense: ambiguous (0.5391); Ultra-rare (popmax 0.0187%, afr); Associated with Inborn genetic diseases.

What condition is associated with EVC2 p.Phe140Leu (c.418T>C)?

EVC2 p.Phe140Leu (c.418T>C) is associated with Inborn genetic diseases, acrofacial dysostosis, Weyers type, Ellis-van Creveld syndrome (ClinVar).

How common is EVC2 p.Phe140Leu (c.418T>C) in the general population?

EVC2 p.Phe140Leu (c.418T>C) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about EVC2 p.Phe140Leu (c.418T>C)?

AlphaMissense predicts ambiguous (score 0.5391) — an in-silico prediction, not a clinical call.

EVC2 p.Phe140Leu

c.418T>C · VCV3846593

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5391 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5391	ambiguous · top 10% in EVC2
REVEL	0.054	moderately benign-leaning
SaProt	LLR -4.50	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -0.6, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	16.45	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 0.0187% African / African-American · 14/74,930 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00904%

Overall 0.00112% 18/1,614,032 alleles · ultra-rare exomes 9/1,461,828 · genomes 9/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,352
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000254%	393,332

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.Phe140Leu
Coding: c.418T>C
MANE Select: NM_147127
Type: single nucleotide variant
Location: chr4:5694367 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acrofacial dysostosis, Weyers type Ellis-van Creveld syndrome

Similar variants

EVC2 p.Phe140fs 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
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-phe140leu (accessed [today's date]).

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