Is ESYT2 p.Phe60Val (c.178T>G) pathogenic?

ESYT2 p.Phe60Val (c.178T>G) is classified Uncertain significance in ESYT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely benign (0.2453); Ultra-rare (popmax 0.0103%, nfe).

How common is ESYT2 p.Phe60Val (c.178T>G) in the general population?

ESYT2 p.Phe60Val (c.178T>G) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about ESYT2 p.Phe60Val (c.178T>G)?

AlphaMissense predicts likely benign (score 0.2453) — an in-silico prediction, not a clinical call.

ESYT2 p.Phe60Val

c.178T>G · VCV3276546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2453 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2453	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -4.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP -3.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 95 kb · p 0.024 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F136V vs ClinVar F60V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 118/1,146,024 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00819%

Overall 0.00792% 121/1,528,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,712
Remaining individualsnot grpmax-eligible	0.00504%	19,845

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: ESYT2
Protein: p.Phe60Val
Coding: c.178T>G
MANE Select: NM_001367773
Type: single nucleotide variant
Location: chr7:158829241 (GRCh38)
Gene constraint: LOEUF 0.684 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.44 · 4 PDB
Residue 60: the 'disordered' region

Full ESYT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ESYT2 c.26C>T Uncertain significance ★ same type
ESYT2 c.43C>G Uncertain significance ★ same type
ESYT2 c.-17C>G Uncertain significance ★ same type
ESYT2 c.-38C>T Uncertain significance ★ ⚠ same type
ESYT2 c.-41A>C Uncertain significance ★ ⚠ same type
ESYT2 c.-55C>G Uncertain significance ★ same type
ESYT2 c.-59G>A Uncertain significance ★ ⚠ same type
ESYT2 c.-62C>G Uncertain significance ★ ⚠ same type

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/esyt2-p-phe60val (accessed [today's date]).

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