Is FLRT3 p.His400Gln (c.1200C>A) pathogenic?

FLRT3 p.His400Gln (c.1200C>A) is classified Benign in FLRT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0739); Common (popmax 48.5%, nfe) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about FLRT3 p.His400Gln (c.1200C>A)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

FLRT3 p.His400Gln

Q: How common is FLRT3 p.His400Gln (c.1200C>A) in the general population?

FLRT3 p.His400Gln (c.1200C>A) is common (popmax 48.5%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1200C>A · rs6079391 · VCV1288590

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 48.5%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -5.51	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 0.94	GERP 0.56, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,946 bp · p 4e-08 · regional, not allelic
Overall
CADD	12.57	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 48.5% European (non-Finnish) · 572,410/1,179,754 alleles

Filtering AF 48.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 48.4%

Overall 44.6% 719,078/1,613,598 alleles · common exomes 660,700/1,461,600 · genomes 58,378/151,998 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	54.5%	2
European (non-Finnish)grpmax	48.5%	2
Ashkenazi Jewishnot grpmax-eligible	45.1%	2
Remaining individualsnot grpmax-eligible	41.8%	2
Admixed American	41.8%	2
Amishnot grpmax-eligible	40.5%	2
Middle Eastern	31.5%	3
South Asian	25.2%	4
African / African-American	19.9%	5
East Asian	16%	6

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: FLRT3
Protein: p.His400Gln
Coding: c.1200C>A
MANE Select: NM_198391
dbSNP: rs6079391
Type: single nucleotide variant
Location: chr20:14326307 (GRCh38)
Gene constraint: LOEUF 0.585 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 74.57 · 3 PDB
Residue 400: the 'disordered' region; a UniProt-annotated variant site (in)

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.Ser33Pro 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

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-his400gln (accessed [today's date]).

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