Is ESAM p.Pro296Thr (c.886C>A) pathogenic?

ESAM p.Pro296Thr (c.886C>A) is classified Uncertain significance in ESAM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-19). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.00534%, nfe).

How common is ESAM p.Pro296Thr (c.886C>A) in the general population?

ESAM p.Pro296Thr (c.886C>A) is very rare (popmax 0.00534%, nfe) (gnomAD).

What do computational predictors say about ESAM p.Pro296Thr (c.886C>A)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

ESAM p.Pro296Thr

c.886C>A · rs773915729 · VCV2328452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,505 bp · p 0.62 · regional, not allelic
Overall
CADD	15.87	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% European (non-Finnish) · 63/1,180,014 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00397% 64/1,613,802 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00534%	18,730
African / African-American	0.00133%	74,912

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: ESAM
Protein: p.Pro296Thr
Coding: c.886C>A
MANE Select: NM_138961
dbSNP: rs773915729
Type: single nucleotide variant
Location: chr11:124753933 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.13
Residue 296: a UniProt-annotated variant site (in nedihss)

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

Similar variants

ESAM p.Val149Ala Uncertain significance ★★ ⚠ same type
ESAM c.731-9C>A Benign ★★ same type
ESAM p.Arg107Trp Likely benign ★★ ⚠ same type
ESAM p.Ile290Val Likely benign ★★ same type
ESAM p.Leu31= Likely benign ★★ same type
ESAM p.Pro181= Likely benign ★★ same type
ESAM c.451+1G>A Likely pathogenic ★ same type
ESAM c.608-1G>A Likely pathogenic ★ 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/esam-p-pro296thr (accessed [today's date]).

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