Is CATIP p.Phe35Ile (c.103T>A) pathogenic?

CATIP p.Phe35Ile (c.103T>A) is classified Likely pathogenic in CATIP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-20). AlphaMissense: ambiguous (0.4611); Ultra-rare (popmax 0.0987%, mid); Associated with spermatogenic failure 54.

What condition is associated with CATIP p.Phe35Ile (c.103T>A)?

CATIP p.Phe35Ile (c.103T>A) is associated with spermatogenic failure 54 (ClinVar).

How common is CATIP p.Phe35Ile (c.103T>A) in the general population?

CATIP p.Phe35Ile (c.103T>A) is ultra-rare (popmax 0.0987%, mid) (gnomAD).

What do computational predictors say about CATIP p.Phe35Ile (c.103T>A)?

AlphaMissense predicts ambiguous (score 0.4611) — an in-silico prediction, not a clinical call.

CATIP p.Phe35Ile

c.103T>A · rs141560868 · VCV1172755

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0987%, mid)

Conditions

spermatogenic failure 54

Computational evidence

Protein change
AlphaMissense	0.4611	ambiguous
REVEL	0.364	indeterminate
SaProt	LLR -10.39	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 11 kb · p 0.75 · regional, not allelic
Overall
CADD	25.8	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 0.0987% Middle Eastern · 6/6,080 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.00979% 158/1,613,364 alleles · ultra-rare exomes 150/1,461,502 · genomes 8/151,862 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
Middle Easterngrpmax	0.0987%	1,013
Remaining individualsnot grpmax-eligible	0.024%	4,164
South Asian	0.0231%	4,336
European (non-Finnish)	0.00915%	10,923
Admixed American	0.00834%	11,987
Finnishnot grpmax-eligible	0.00156%	63,978
African / African-American	0.00134%	74,784

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CATIP
Protein: p.Phe35Ile
Coding: c.103T>A
MANE Select: NM_198559
dbSNP: rs141560868
Type: single nucleotide variant
Location: chr2:218357172 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.37
Residue 35: a UniProt-annotated variant site (in spgf54; reduces the protein stability. increases the kinetics of actin polymerization)

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

Disease context

spermatogenic failure 54 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CATIP p.Ala363Thr Uncertain significance ★★ ⚠ same type
CATIP p.Ser57Leu Uncertain significance ★★ ⚠ same type
CATIP p.Ala348Thr Uncertain significance ★ ⚠ same type
CATIP p.Arg187Gln Uncertain significance ★ ⚠ same type
CATIP p.Arg195Cys Uncertain significance ★ ⚠ same type
CATIP p.Arg311Gln Uncertain significance ★ ⚠ same type
CATIP p.Arg383Gly Uncertain significance ★ ⚠ same type
CATIP p.Arg93Gln 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/catip-p-phe35ile (accessed [today's date]).

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