Is ENOSF1 p.Ser405Pro (c.1213T>C) pathogenic?

ENOSF1 p.Ser405Pro (c.1213T>C) is classified Uncertain significance in ENOSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-17). AlphaMissense: likely pathogenic (0.7996); Ultra-rare (popmax 0.0736%, amr).

How common is ENOSF1 p.Ser405Pro (c.1213T>C) in the general population?

ENOSF1 p.Ser405Pro (c.1213T>C) is ultra-rare (popmax 0.0736%, amr) (gnomAD).

What do computational predictors say about ENOSF1 p.Ser405Pro (c.1213T>C)?

AlphaMissense predicts likely pathogenic (score 0.7996) — an in-silico prediction, not a clinical call.

ENOSF1 p.Ser405Pro

c.1213T>C · rs766984806 · VCV2385099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7996 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0736%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7996	likely pathogenic
REVEL	0.104	moderately benign-leaning
SaProt	LLR -10.15	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -0.67, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 38 kb · p 0.14 · regional, not allelic
Overall
CADD	20.2	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 0.0736% Admixed American · 44/59,756 alleles

Filtering AF 0.0563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0502%

Overall 0.00298% 48/1,612,088 alleles · ultra-rare exomes 32/1,459,852 · genomes 16/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0736%	1,358
Remaining individualsnot grpmax-eligible	0.0016%	62,434
European (non-Finnish)	0.000254%	393,193

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.Ser405Pro
Coding: c.1213T>C
MANE Select: NM_017512
dbSNP: rs766984806
Type: single nucleotide variant
Location: chr18:675338 (GRCh38)
Gene constraint: LOEUF 1.236 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.47 · 1 PDB
Residue 405: 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-ser405pro (accessed [today's date]).

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