Is PLXNA3 p.Ser671Phe (c.2012C>T) pathogenic?

PLXNA3 p.Ser671Phe (c.2012C>T) is classified Uncertain significance in PLXNA3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-01-18). AlphaMissense: likely benign (0.2912); Ultra-rare (popmax 0.0209%, afr).

How common is PLXNA3 p.Ser671Phe (c.2012C>T) in the general population?

PLXNA3 p.Ser671Phe (c.2012C>T) is ultra-rare (popmax 0.0209%, afr) (gnomAD).

What do computational predictors say about PLXNA3 p.Ser671Phe (c.2012C>T)?

AlphaMissense predicts likely benign (score 0.2912) — an in-silico prediction, not a clinical call.

PLXNA3 p.Ser671Phe

c.2012C>T · rs148224862 · VCV2361039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2912 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2912	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -10.99	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 4,918 bp · p 5.4e-08 · regional, not allelic
Overall
CADD	21.9	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 0.0209% African / African-American · 12/57,329 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00937%

Overall 0.00116% 14/1,204,796 alleles · ultra-rare exomes 4/1,092,329 · genomes 10/112,467 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0209%	4,777
Admixed American	0.00219%	45,690
European (non-Finnish)	0.000112%	891,838

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: PLXNA3
Protein: p.Ser671Phe
Coding: c.2012C>T
MANE Select: NM_017514
dbSNP: rs148224862
Type: single nucleotide variant
Location: chrX:154464837 (GRCh38)
Structure: AlphaFold pLDDT 84.77

Full PLXNA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLXNA3 p.Arg1061His Uncertain significance ★★ ⚠ same type
PLXNA3 p.Arg519Leu Uncertain significance ★★ ⚠ same type
PLXNA3 p.Asn1009Thr Uncertain significance ★★ ⚠ same type
PLXNA3 p.Asp981Ala Uncertain significance ★★ ⚠ same type
PLXNA3 p.His88Tyr Uncertain significance ★★ ⚠ same type
PLXNA3 p.Leu339Val Uncertain significance ★★ ⚠ same type
PLXNA3 p.Leu761Pro Uncertain significance ★★ ⚠ same type
PLXNA3 p.Ser175Leu 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/plxna3-p-ser671phe (accessed [today's date]).

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