Is FAN1 p.Pro103Gln (c.308C>A) pathogenic?

FAN1 p.Pro103Gln (c.308C>A) is classified Uncertain significance in FAN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-16). AlphaMissense: likely benign (0.0747); Ultra-rare (popmax 0.0172%, nfe); Associated with karyomegalic interstitial nephritis.

What condition is associated with FAN1 p.Pro103Gln (c.308C>A)?

FAN1 p.Pro103Gln (c.308C>A) is associated with karyomegalic interstitial nephritis (ClinVar).

How common is FAN1 p.Pro103Gln (c.308C>A) in the general population?

FAN1 p.Pro103Gln (c.308C>A) is ultra-rare (popmax 0.0172%, nfe) (gnomAD).

How is Karyomegalic interstitial nephritis inherited?

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

What do computational predictors say about FAN1 p.Pro103Gln (c.308C>A)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

FAN1 p.Pro103Gln

c.308C>A · rs200672666 · VCV2071131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

karyomegalic interstitial nephritis

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -6.15	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 2	GERP 0.56, phastCons 0.05
Regional constraint	o/e 1.19	unconstrained · MANE · 6,048 bp · p 3.5e-06 · regional, not allelic
Overall
CADD	7.017	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 0.0172% European (non-Finnish) · 203/1,179,968 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0145%

Overall 0.0131% 212/1,613,798 alleles · ultra-rare exomes 199/1,461,722 · genomes 13/152,076 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0172%	5,813
African / African-American	0.00534%	18,719
Remaining individualsnot grpmax-eligible	0.0048%	20,828
East Asian	0.00446%	22,443

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: FAN1
Protein: p.Pro103Gln
Coding: c.308C>A
MANE Select: NM_014967
dbSNP: rs200672666
Type: single nucleotide variant
Location: chr15:30904971 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.71 · 20 PDB
Residue 103: the 'disordered' region

Full FAN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

karyomegalic interstitial nephritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Karyomegalic interstitial nephritis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult

Similar variants

FAN1 c.1375+1G>A Pathogenic/Likely pathogenic ★★ same condition
FAN1 c.1943+1G>A Pathogenic/Likely pathogenic ★★ same condition
FAN1 p.Arg710Ter Pathogenic/Likely pathogenic ★★ same condition
FAN1 p.Arg754Ter Pathogenic/Likely pathogenic ★★ same condition
FAN1 p.Cys47Ter Pathogenic/Likely pathogenic ★★ same condition
FAN1 p.Gln457Ter Pathogenic ★★ same condition
FAN1 p.Trp707Ter Pathogenic ★★ same condition
FAN1 p.Ala40Gly 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/fan1-p-pro103gln (accessed [today's date]).

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