Is FRK p.Arg42Ser (c.126G>T) pathogenic?

FRK p.Arg42Ser (c.126G>T) is classified Uncertain significance in FRK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1184); Ultra-rare (popmax 0.035%, amr).

How common is FRK p.Arg42Ser (c.126G>T) in the general population?

FRK p.Arg42Ser (c.126G>T) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about FRK p.Arg42Ser (c.126G>T)?

AlphaMissense predicts likely benign (score 0.1184) — an in-silico prediction, not a clinical call.

FRK p.Arg42Ser

c.126G>T · rs200539604 · VCV2510935

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1184 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1184	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -4.86	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 0.017	GERP -3.5
Regional constraint	o/e 0.95	unconstrained · MANE · 118 kb · p 0.2 · regional, not allelic
Overall
CADD	3.477	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 0.035% Admixed American · 21/60,020 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0026% 42/1,614,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,858
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)	0.00136%	73,752

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: FRK
Protein: p.Arg42Ser
Coding: c.126G>T
MANE Select: NM_002031
dbSNP: rs200539604
Type: single nucleotide variant
Location: chr6:116060186 (GRCh38)
Gene constraint: LOEUF 1.016 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.41
Residue 42: the sh3 domain

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

Similar variants

FRK p.Arg42Met Uncertain significance ★ ⚠ same residue
FRK p.Ala160Ser Uncertain significance ★ ⚠ same type
FRK p.Arg143Gly Uncertain significance ★ ⚠ same type
FRK p.Arg179Gln Uncertain significance ★ ⚠ same type
FRK p.Arg377Gly Uncertain significance ★ ⚠ same type
FRK p.Arg406His Uncertain significance ★ ⚠ same type
FRK p.Arg89Leu Uncertain significance ★ ⚠ same type
FRK p.Asn135Lys 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/frk-p-arg42ser (accessed [today's date]).

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