Is CNTNAP5 p.Phe751Ser (c.2252T>C) pathogenic?

CNTNAP5 p.Phe751Ser (c.2252T>C) is classified Uncertain significance in CNTNAP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1934); Very rare (popmax 0.00136%, nfe).

How common is CNTNAP5 p.Phe751Ser (c.2252T>C) in the general population?

CNTNAP5 p.Phe751Ser (c.2252T>C) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about CNTNAP5 p.Phe751Ser (c.2252T>C)?

AlphaMissense predicts likely benign (score 0.1934) — an in-silico prediction, not a clinical call.

CNTNAP5 p.Phe751Ser

c.2252T>C · rs1265414749 · VCV2395675

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1934	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -8.50	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 5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 889 kb · p 0.81 · regional, not allelic
Overall
CADD	23.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F750S vs ClinVar F751S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,162 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,612,470 alleles · very rare

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: CNTNAP5
Protein: p.Phe751Ser
Coding: c.2252T>C
MANE Select: NM_001367498
dbSNP: rs1265414749
Type: single nucleotide variant
Location: chr2:124763689 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 84.06
Residue 751: the fibrinogen c-terminal domain

Full CNTNAP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNTNAP5 p.Arg1182His Uncertain significance ★★ ⚠ same type
CNTNAP5 p.Arg1261Trp Uncertain significance ★★ ⚠ same type
CNTNAP5 c.1328-7C>T Benign ★★ same type
CNTNAP5 p.Ala1187Thr Benign ★★ same type
CNTNAP5 p.Ala602= Benign/Likely benign ★★ same type
CNTNAP5 p.Asn27Thr Benign ★★ same type
CNTNAP5 p.Asp693Gly Likely benign ★★ same type
CNTNAP5 p.Glu1130= 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/cntnap5-p-phe751ser (accessed [today's date]).

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