Is CIROP p.Ser31Phe (c.92C>T) pathogenic?

CIROP p.Ser31Phe (c.92C>T) is classified Conflicting classifications of pathogenicity in CIROP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.2754); Rare (popmax 0.19%, nfe); Associated with heterotaxy, visceral, 12, autosomal.

What condition is associated with CIROP p.Ser31Phe (c.92C>T)?

CIROP p.Ser31Phe (c.92C>T) is associated with heterotaxy, visceral, 12, autosomal (ClinVar).

How common is CIROP p.Ser31Phe (c.92C>T) in the general population?

CIROP p.Ser31Phe (c.92C>T) is rare (popmax 0.19%, nfe) (gnomAD).

What do computational predictors say about CIROP p.Ser31Phe (c.92C>T)?

AlphaMissense predicts likely benign (score 0.2754) — an in-silico prediction, not a clinical call.

CIROP p.Ser31Phe

c.92C>T · rs553352307 · VCV1335920

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2754 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.19%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

heterotaxy, visceral, 12, autosomal

Computational evidence

Protein change
AlphaMissense	0.2754	likely benign
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.87 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 2.2, phastCons 1
Regional constraint	o/e 1.77	unconstrained · MANE · 5,635 bp · p 1.3e-32 · regional, not allelic
Overall
CADD	22.6	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 0.19% European (non-Finnish) · 732/384,966 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.174%

Overall 0.129% 907/702,970 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.19%	526
Middle Eastern	0.183%	546
Remaining individualsnot grpmax-eligible	0.144%	697
South Asian	0.0976%	1,024
Admixed American	0.056%	1,786
African / African-American	0.0401%	2,492
Ashkenazi Jewishnot grpmax-eligible	0.00852%	11,738
Finnishnot grpmax-eligible	0.00226%	44,314

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: CIROP
Protein: p.Ser31Phe
Coding: c.92C>T
MANE Select: NM_001354640
dbSNP: rs553352307
Type: single nucleotide variant
Location: chr14:23104829 (GRCh38)
Structure: AlphaFold pLDDT 73.73
Residue 31: a UniProt-annotated variant site (in htx12; uncertain significance)

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

Disease context

heterotaxy, visceral, 12, autosomal — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CIROP p.Gln528Ter Likely pathogenic ★ same condition
CIROP p.Arg22Ter Conflicting classifications of pathogenicity ★ same condition
CIROP p.Gly180Arg Uncertain significance ★ ⚠ same condition
CIROP p.Gly511Glu Uncertain significance ★ ⚠ same condition
CIROP p.Tyr68Cys Uncertain significance ★ ⚠ same condition
CIROP p.Arg191Ter Pathogenic same condition
CIROP p.Arg389Ile Pathogenic same condition
CIROP p.Ser384Leu Pathogenic 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/cirop-p-ser31phe (accessed [today's date]).

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