Is ENOSF1 p.Thr246Ala (c.736A>G) pathogenic?

ENOSF1 p.Thr246Ala (c.736A>G) is classified Uncertain significance in ENOSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0864); Ultra-rare (popmax 0.0165%, mid).

How common is ENOSF1 p.Thr246Ala (c.736A>G) in the general population?

ENOSF1 p.Thr246Ala (c.736A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ENOSF1 p.Thr246Ala (c.736A>G)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

ENOSF1 p.Thr246Ala

c.736A>G · VCV4249116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -7.07	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 3.3	GERP -0.78, phastCons 0.98
Regional constraint	o/e 1.06	unconstrained · MANE · 38 kb · p 0.14 · regional, not allelic
Overall
CADD	15.89	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00155% 25/1,613,310 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00666%	15,009
Remaining individualsnot grpmax-eligible	0.0048%	20,824
European (non-Finnish)	0.00127%	78,617
South Asian	0.0011%	91,062

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.Thr246Ala
Coding: c.736A>G
MANE Select: NM_017512
Type: single nucleotide variant
Location: chr18:685926 (GRCh38)
Gene constraint: LOEUF 1.236 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.47 · 1 PDB
Residue 246: a β-strand

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-thr246ala (accessed [today's date]).

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