Is ENOSF1 p.Pro243Leu (c.728C>T) pathogenic?

ENOSF1 p.Pro243Leu (c.728C>T) is classified Uncertain significance in ENOSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0836); Ultra-rare (popmax 0.0167%, amr).

How common is ENOSF1 p.Pro243Leu (c.728C>T) in the general population?

ENOSF1 p.Pro243Leu (c.728C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about ENOSF1 p.Pro243Leu (c.728C>T)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

ENOSF1 p.Pro243Leu

c.728C>T · rs766220285 · VCV3088925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -8.73	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 8.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 38 kb · p 0.14 · regional, not allelic
Overall
CADD	22.2	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 0.0167% Admixed American · 10/59,988 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00217% 35/1,613,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
South Asian	0.00329%	30,358
East Asian	0.00223%	44,838
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	0.00153%	65,539
African / African-American	0.00134%	74,876

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: ENOSF1
Protein: p.Pro243Leu
Coding: c.728C>T
MANE Select: NM_017512
dbSNP: rs766220285
Type: single nucleotide variant
Location: chr18:685934 (GRCh38)
Gene constraint: LOEUF 1.236 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.47 · 1 PDB

Full ENOSF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENOSF1 c.*1219T>C Benign ★★ same type
TYMS c.556+1G>A Pathogenic ★ same type
TYMS p.Arg271Ter Pathogenic ★ same type
ENOSF1 c.84+108G>C Uncertain significance ★ same type
ENOSF1 c.84+112A>C Uncertain significance ★ same type
ENOSF1 c.84+114C>G Uncertain significance ★ same type
ENOSF1 c.84+125T>C Uncertain significance ★ same type
ENOSF1 c.84+130A>C 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/enosf1-p-pro243leu (accessed [today's date]).

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