Is FANCF p.His43Pro (c.128A>C) pathogenic?

FANCF p.His43Pro (c.128A>C) is classified Uncertain significance in FANCF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.6454); Very rare (popmax 0.000763%, nfe); Associated with Fanconi anemia.

What condition is associated with FANCF p.His43Pro (c.128A>C)?

FANCF p.His43Pro (c.128A>C) is associated with Fanconi anemia (ClinVar).

How common is FANCF p.His43Pro (c.128A>C) in the general population?

FANCF p.His43Pro (c.128A>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

How is Hereditary isolated aplastic anemia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FANCF p.His43Pro (c.128A>C)?

AlphaMissense predicts likely pathogenic (score 0.6454) — an in-silico prediction, not a clinical call.

FANCF p.His43Pro

c.128A>C · rs761221734 · VCV574144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6454 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fanconi anemia

Computational evidence

Protein change
AlphaMissense	0.6454	likely pathogenic
REVEL	0.232	benign-leaning
SaProt	LLR -10.05	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 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,121 bp · p 0.0014 · regional, not allelic
Overall
CADD	24.1	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 0.000763% European (non-Finnish) · 9/1,180,002 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00235% 38/1,613,922 alleles · very rare exomes 37/1,461,694 · genomes 1/152,228 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0913%	1,096
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)grpmax	0.000763%	131,111

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FANCF
Protein: p.His43Pro
Coding: c.128A>C
MANE Select: NM_022725
dbSNP: rs761221734
Type: single nucleotide variant
Location: chr11:22625683 (GRCh38)
Structure: AlphaFold pLDDT 78.87 · 7 PDB
Residue 43: an α-helix

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

Disease context

Fanconi anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary isolated aplastic anemia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

FANCF p.Gln65Ter Likely pathogenic ★★ same condition
FANCF p.Glu220Ter Pathogenic/Likely pathogenic ★★ same condition
FANCF p.Glu223Ter Pathogenic/Likely pathogenic ★★ same condition
FANCF p.Met1Arg Pathogenic/Likely pathogenic ★★ same condition
FANCF p.Ala124Ser Uncertain significance ★★ ⚠ same condition
FANCF p.Ala206Val Uncertain significance ★★ ⚠ same condition
FANCF p.Ala334Val Uncertain significance ★★ ⚠ same condition
FANCF p.Ala34Val Uncertain significance ★★ ⚠ same condition

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/fancf-p-his43pro (accessed [today's date]).

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