Is FLRT3 p.Ser33Pro (c.97T>C) pathogenic?

FLRT3 p.Ser33Pro (c.97T>C) is classified Uncertain significance in FLRT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-16). AlphaMissense: likely benign (0.0826); Ultra-rare (popmax 0.0201%, eas).

How common is FLRT3 p.Ser33Pro (c.97T>C) in the general population?

FLRT3 p.Ser33Pro (c.97T>C) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about FLRT3 p.Ser33Pro (c.97T>C)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

FLRT3 p.Ser33Pro

c.97T>C · VCV4668946

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.44	indeterminate
SaProt	LLR -7.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.97, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	20.6	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 0.0201% East Asian · 9/44,864 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00192% 31/1,613,576 alleles · ultra-rare exomes 27/1,461,436 · genomes 4/152,140 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.032%	3,123
East Asiangrpmax	0.0201%	4,985
Admixed American	0.00334%	29,982

Remaining individuals 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: FLRT3
Protein: p.Ser33Pro
Coding: c.97T>C
MANE Select: NM_198391
Type: single nucleotide variant
Location: chr20:14327410 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB
Residue 33: the lrrnt domain

Full FLRT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FLRT3 p.Arg163Cys Uncertain significance ★★ ⚠ same type
FLRT3 p.Leu109Val Uncertain significance ★★ ⚠ same type
FLRT3 p.Ser25Pro Uncertain significance ★★ ⚠ same type
FLRT3 p.Ser284Arg Uncertain significance ★★ ⚠ same type
FLRT3 p.Thr199Ser Uncertain significance ★★ ⚠ same type
FLRT3 p.Thr419Ser Uncertain significance ★★ ⚠ same type
FLRT3 p.Trp381Arg Uncertain significance ★★ ⚠ same type
FLRT3 p.Ala377Thr Benign/Likely benign ★★ 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/flrt3-p-ser33pro (accessed [today's date]).

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