Is FRS2 p.Ser331Leu (c.992C>T) pathogenic?

FRS2 p.Ser331Leu (c.992C>T) is classified Uncertain significance in FRS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-14). AlphaMissense: likely benign (0.0729); Absent from gnomAD v4.1.

How common is FRS2 p.Ser331Leu (c.992C>T) in the general population?

FRS2 p.Ser331Leu (c.992C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FRS2 p.Ser331Leu (c.992C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

FRS2 p.Ser331Leu

c.992C>T · rs2498959120 · VCV3097044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 3,611 bp · p 0.03 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FRS2
Protein: p.Ser331Leu
Coding: c.992C>T
MANE Select: NM_001278356
dbSNP: rs2498959120
Type: single nucleotide variant
Location: chr12:69574420 (GRCh38)
Gene constraint: LOEUF 0.392 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.98 · 2 PDB
Residue 331: the 'disordered' region

Full FRS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FRS2 c.576+1G>T Uncertain significance ★ same type
FRS2 p.Ala218Val Uncertain significance ★ ⚠ same type
FRS2 p.Ala223Thr Uncertain significance ★ ⚠ same type
FRS2 p.Ala92Asp Uncertain significance ★ ⚠ same type
FRS2 p.Arg134Gln Uncertain significance ★ ⚠ same type
FRS2 p.Arg206Gln Uncertain significance ★ ⚠ same type
FRS2 p.Arg209Cys Uncertain significance ★ ⚠ same type
FRS2 p.Arg209His 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/frs2-p-ser331leu (accessed [today's date]).

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