Is CNFN p.Cys61Ser (c.181T>A) pathogenic?

CNFN p.Cys61Ser (c.181T>A) is classified Uncertain significance in CNFN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.5859); Ultra-rare (popmax 0.0255%, amr).

How common is CNFN p.Cys61Ser (c.181T>A) in the general population?

CNFN p.Cys61Ser (c.181T>A) is ultra-rare (popmax 0.0255%, amr) (gnomAD).

What do computational predictors say about CNFN p.Cys61Ser (c.181T>A)?

AlphaMissense predicts likely pathogenic (score 0.5859) — an in-silico prediction, not a clinical call.

CNFN p.Cys61Ser

c.181T>A · rs758089800 · VCV3146429

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5859 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0255%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5859	likely pathogenic
REVEL	0.509	indeterminate
SaProt	LLR -13.43	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 9	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,881 bp · p 0.32 · regional, not allelic
Overall
CADD	26.4	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 0.0255% Admixed American · 15/58,736 alleles

Filtering AF 0.0157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0127%

Overall 0.00144% 23/1,602,242 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0255%	3,916
Remaining individualsnot grpmax-eligible	0.00647%	15,462
European (non-Finnish)	0.00034%	293,991

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: CNFN
Protein: p.Cys61Ser
Coding: c.181T>A
MANE Select: NM_032488
dbSNP: rs758089800
Type: single nucleotide variant
Location: chr19:42387408 (GRCh38)
Gene constraint: LOEUF 1.457 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.22

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

Similar variants

CNFN p.Ala49Ser Uncertain significance ★ ⚠ same type
CNFN p.Ala91Ser Uncertain significance ★ ⚠ same type
CNFN p.Ala91Val Uncertain significance ★ ⚠ same type
CNFN p.Asp55Asn Uncertain significance ★ ⚠ same type
CNFN p.Cys11Gly Uncertain significance ★ ⚠ same type
CNFN p.Cys47Phe Uncertain significance ★ ⚠ same type
CNFN p.Cys59Gly Uncertain significance ★ ⚠ same type
CNFN p.Gly27Ala 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/cnfn-p-cys61ser (accessed [today's date]).

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