Is EVC p.Phe531Leu (c.1593C>G) pathogenic?

EVC p.Phe531Leu (c.1593C>G) is classified Uncertain significance in EVC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely pathogenic (0.9076); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with EVC p.Phe531Leu (c.1593C>G)?

EVC p.Phe531Leu (c.1593C>G) is associated with Inborn genetic diseases (ClinVar).

How common is EVC p.Phe531Leu (c.1593C>G) in the general population?

EVC p.Phe531Leu (c.1593C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EVC p.Phe531Leu (c.1593C>G)?

AlphaMissense predicts likely pathogenic (score 0.9076) — an in-silico prediction, not a clinical call.

EVC p.Phe531Leu

c.1593C>G · VCV4020157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9076	likely pathogenic · top 1% in EVC
REVEL	0.258	benign-leaning
SaProt	LLR 0.42	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.68, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 100 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	21.1	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 0.00133% African / African-American · 1/74,912 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,614,020 alleles · very rare exomes 11/1,461,886 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,912
European (non-Finnish)	0.00102%	98,335

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.Phe531Leu
Coding: c.1593C>G
MANE Select: NM_153717
Type: single nucleotide variant
Location: chr4:5783581 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.49

Full EVC 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

Similar variants

EVC p.Phe531= Likely benign ★ same residue
EVC p.Ala20Pro Uncertain significance ★★ ⚠ same condition
EVC p.Ala365Asp Uncertain significance ★★ ⚠ same condition
EVC p.Ala365Thr Uncertain significance ★★ ⚠ same condition
EVC p.Arg340Gln Uncertain significance ★★ ⚠ same condition
EVC p.Arg438Trp Uncertain significance ★★ ⚠ same condition
EVC p.Arg622Gln Uncertain significance ★★ ⚠ same condition
EVC p.Arg647Trp Uncertain significance ★★ ⚠ 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-phe531leu (accessed [today's date]).

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