Is FER p.Ile748Val (c.2242A>G) pathogenic?

FER p.Ile748Val (c.2242A>G) is classified Uncertain significance in FER (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely benign (0.0983); Ultra-rare (popmax 0.0165%, mid).

How common is FER p.Ile748Val (c.2242A>G) in the general population?

FER p.Ile748Val (c.2242A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about FER p.Ile748Val (c.2242A>G)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

FER p.Ile748Val

c.2242A>G · VCV3514615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -5.79	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 6.2	phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,773 bp · p 0.21 · regional, not allelic
Overall
CADD	20.5	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00793% 128/1,614,118 alleles · ultra-rare exomes 104/1,461,846 · genomes 24/152,272 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0984%	1,016
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00517%	19,344
Remaining individualsnot grpmax-eligible	0.0032%	31,254
Admixed American	0.00167%	60,026

Finnish 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: FER
Protein: p.Ile748Val
Coding: c.2242A>G
MANE Select: NM_005246
Type: single nucleotide variant
Location: chr5:109186238 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.29 · 2 PDB
Residue 748: the protein kinase domain

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

Similar variants

FER p.Ala272Thr Uncertain significance ★ ⚠ same type
FER p.Ala313Gly Uncertain significance ★ ⚠ same type
FER p.Ala438Ser Uncertain significance ★ ⚠ same type
FER p.Ala89Thr Uncertain significance ★ ⚠ same type
FER p.Arg417Ser Uncertain significance ★ ⚠ same type
FER p.Arg707His Uncertain significance ★ ⚠ same type
FER p.Asn148Ile Uncertain significance ★ ⚠ same type
FER p.Asn261Ser 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/fer-p-ile748val (accessed [today's date]).

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