Is CNTNAP1 p.Arg925Cys (c.2773C>T) pathogenic?

CNTNAP1 p.Arg925Cys (c.2773C>T) is classified Uncertain significance in CNTNAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.7951); Ultra-rare (popmax 0.0493%, mid); Associated with Inborn genetic diseases.

What condition is associated with CNTNAP1 p.Arg925Cys (c.2773C>T)?

CNTNAP1 p.Arg925Cys (c.2773C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNTNAP1 p.Arg925Cys (c.2773C>T) in the general population?

CNTNAP1 p.Arg925Cys (c.2773C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about CNTNAP1 p.Arg925Cys (c.2773C>T)?

AlphaMissense predicts likely pathogenic (score 0.7951) — an in-silico prediction, not a clinical call.

CNTNAP1 p.Arg925Cys

c.2773C>T · rs755673095 · VCV2073123

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7951 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7951	likely pathogenic
REVEL	0.616	indeterminate
SaProt	LLR -10.69	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 15 kb · p 9.7e-20 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00186% 30/1,614,074 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
South Asian	0.0165%	6,073
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
East Asian	0.00446%	22,444
African / African-American	0.00267%	37,471
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000339%	295,008

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: CNTNAP1
Protein: p.Arg925Cys
Coding: c.2773C>T
MANE Select: NM_003632
dbSNP: rs755673095
Type: single nucleotide variant
Location: chr17:42693317 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 925: the laminin g-like 3 domain; a UniProt-annotated variant site (in chn3); a UniProt-annotated variant site (in lccs7 and chn3); a UniProt-annotated variant site (in lccs7)

Full CNTNAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNTNAP1 p.Ala1322Thr Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Ala254Thr Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Ala40Thr Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Ala887Val Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1022Ser Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1073His Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1150Cys Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1153Gln Uncertain significance ★★ ⚠ same condition

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/cntnap1-p-arg925cys (accessed [today's date]).

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