Is EVC2 p.Ser309Phe (c.926C>T) pathogenic?

EVC2 p.Ser309Phe (c.926C>T) is classified Uncertain significance in EVC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-08). AlphaMissense: ambiguous (0.4651); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with EVC2 p.Ser309Phe (c.926C>T)?

EVC2 p.Ser309Phe (c.926C>T) is associated with Inborn genetic diseases (ClinVar).

How common is EVC2 p.Ser309Phe (c.926C>T) in the general population?

EVC2 p.Ser309Phe (c.926C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about EVC2 p.Ser309Phe (c.926C>T)?

AlphaMissense predicts ambiguous (score 0.4651) — an in-silico prediction, not a clinical call.

EVC2 p.Ser309Phe

c.926C>T · VCV3510674

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4651	ambiguous
REVEL	0.37	indeterminate
SaProt	LLR -6.24	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP 0.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 146 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	24.4	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 · 1/74,944 alleles

Overall 0.000186% 3/1,614,116 alleles · very rare exomes 2/1,461,892 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-Americangrpmax	0.00133%	74,944
European (non-Finnish)	8.47e-05%	1,180,044

Remaining individuals 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.Ser309Phe
Coding: c.926C>T
MANE Select: NM_147127
Type: single nucleotide variant
Location: chr4:5665594 (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

Similar variants

EVC2 p.Ser309= Likely benign ★ same residue
EVC2 p.Gln1089Ter Pathogenic ★★ same condition
EVC2 p.Ala1132Val Uncertain significance ★★ ⚠ same condition
EVC2 p.Ala1150Asp Uncertain significance ★★ ⚠ same condition
EVC2 p.Ala1260Val Uncertain significance ★★ ⚠ same condition
EVC2 p.Ala618Thr Uncertain significance ★★ ⚠ same condition
EVC2 p.Ala703Val Uncertain significance ★★ ⚠ same condition
EVC2 p.Arg1140Cys 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/evc2-p-ser309phe (accessed [today's date]).

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