Is CAPSL p.Phe61Val (c.181T>G) pathogenic?

CAPSL p.Phe61Val (c.181T>G) is classified Uncertain significance in CAPSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1556); Ultra-rare (popmax 0.076%, afr).

How common is CAPSL p.Phe61Val (c.181T>G) in the general population?

CAPSL p.Phe61Val (c.181T>G) is ultra-rare (popmax 0.076%, afr) (gnomAD).

What do computational predictors say about CAPSL p.Phe61Val (c.181T>G)?

AlphaMissense predicts likely benign (score 0.1556) — an in-silico prediction, not a clinical call.

CAPSL p.Phe61Val

c.181T>G · rs114583055 · VCV2467906

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1556 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.076%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1556	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.29	acceptor loss, 7 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 17 kb · p 0.065 · regional, not allelic
Overall
CADD	23.4	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.076% African / African-American · 57/75,014 alleles

Filtering AF 0.0601% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0545%

Overall 0.00397% 64/1,612,362 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.076%	1,316
Remaining individualsnot grpmax-eligible	0.00481%	20,809
Admixed American	0.00334%	29,962
European (non-Finnish)	0.00017%	589,438

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: CAPSL
Protein: p.Phe61Val
Coding: c.181T>G
MANE Select: NM_001042625
dbSNP: rs114583055
Type: single nucleotide variant
Location: chr5:35910500 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB
Residue 61: the ef-hand 1 domain

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

Similar variants

CAPSL p.Met201Val Benign ★★ ⚠ same type
CAPSL p.Ala2Ser Uncertain significance ★ ⚠ same type
CAPSL p.Arg137Cys Uncertain significance ★ ⚠ same type
CAPSL p.Arg137His Uncertain significance ★ ⚠ same type
CAPSL p.Arg137Leu Uncertain significance ★ ⚠ same type
CAPSL p.Arg160Thr Uncertain significance ★ ⚠ same type
CAPSL p.Asp135Glu Uncertain significance ★ ⚠ same type
CAPSL p.Asp60Ala 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/capsl-p-phe61val (accessed [today's date]).

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