Is LEF1 p.Pro25Ser (c.73C>T) pathogenic?

LEF1 p.Pro25Ser (c.73C>T) is classified Uncertain significance in LEF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-14). AlphaMissense: likely benign (0.1517); Very rare (popmax 0.00891%, eas).

How common is LEF1 p.Pro25Ser (c.73C>T) in the general population?

LEF1 p.Pro25Ser (c.73C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about LEF1 p.Pro25Ser (c.73C>T)?

AlphaMissense predicts likely benign (score 0.1517) — an in-silico prediction, not a clinical call.

LEF1 p.Pro25Ser

c.73C>T · rs201163073 · VCV2623984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1517 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1517	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -5.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 89 kb · p 0.0049 · 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 0.00891% East Asian · 4/44,874 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,614,170 alleles · very rare exomes 3/1,461,840 · genomes 1/152,330 · joint denominator

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: LEF1
Protein: p.Pro25Ser
Coding: c.73C>T
MANE Select: NM_016269
dbSNP: rs201163073
Type: single nucleotide variant
Location: chr4:108167695 (GRCh38)
Gene constraint: LOEUF 0.459 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.74
Residue 25: the 'disordered' region; the 'ctnnb1-binding' region

Full LEF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LEF1 p.Asp85Asn Benign/Likely benign ★★ same type
LEF1 p.Ser109= Benign ★★ same type
LEF1 p.Ala305Thr Uncertain significance ★ ⚠ same type
LEF1 p.Ala352Thr Uncertain significance ★ ⚠ same type
LEF1 p.Arg296Lys Uncertain significance ★ ⚠ same type
LEF1 p.Asn59Lys Uncertain significance ★ ⚠ same type
LEF1 p.Asp177Val Uncertain significance ★ ⚠ same type
LEF1 p.Asp276Asn 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/lef1-p-pro25ser (accessed [today's date]).

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