Is F3 p.Pro111Leu (c.332C>T) pathogenic?

F3 p.Pro111Leu (c.332C>T) is classified Uncertain significance in F3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1045); Ultra-rare (popmax 0.036%, afr).

How common is F3 p.Pro111Leu (c.332C>T) in the general population?

F3 p.Pro111Leu (c.332C>T) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about F3 p.Pro111Leu (c.332C>T)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

F3 p.Pro111Leu

c.332C>T · VCV4020738

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.128	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 -0.025	GERP -1.8
Overall
CADD	6.04	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 0.036% African / African-American · 27/74,902 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00273% 44/1,613,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,774
Remaining individualsnot grpmax-eligible	0.0032%	31,243
East Asian	0.00223%	44,882
South Asian	0.0022%	45,539
European (non-Finnish)	0.00102%	98,334

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: F3
Protein: p.Pro111Leu
Coding: c.332C>T
MANE Select: NM_001843 · reported on NM_001993
Type: single nucleotide variant
Location: chr1:94536045 (GRCh38)
Structure: AlphaFold pLDDT 87.29 · 2 PDB
Residue 111: a disulfide bond; the ig-like c2-type 1 domain

Full F3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNTN1 p.Ile111Met Uncertain significance ★ ⚠ same residue
CNTN1 p.Ala410Val Uncertain significance ★★ ⚠ same type
CNTN1 p.Ala514Thr Uncertain significance ★★ ⚠ same type
CNTN1 p.Ala528Val Uncertain significance ★★ ⚠ same type
CNTN1 p.Ala668Thr Uncertain significance ★★ ⚠ same type
CNTN1 p.Ala799Thr Uncertain significance ★★ ⚠ same type
CNTN1 p.Ala930Ser Uncertain significance ★★ ⚠ same type
CNTN1 p.Ala995Thr 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/f3-p-pro111leu (accessed [today's date]).

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