Is IQCE p.Pro135= (c.405T>C) pathogenic?

IQCE p.Pro135= (c.405T>C) is classified Benign in IQCE (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-19). Common (popmax 14.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with polydactyly, postaxial, type a7.

What condition is associated with IQCE p.Pro135= (c.405T>C)?

IQCE p.Pro135= (c.405T>C) is associated with polydactyly, postaxial, type a7 (ClinVar).

IQCE p.Pro135=

Q: How common is IQCE p.Pro135= (c.405T>C) in the general population?

IQCE p.Pro135= (c.405T>C) is common (popmax 14.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.405T>C · rs61739566 · VCV1300117

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 14.4%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

polydactyly, postaxial, type a7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -2.7
Overall
CADD	2.133	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.4% European (non-Finnish) · 150,399/1,047,288 alleles

Filtering AF 14.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.3%

Overall 13.6% 199,772/1,467,512 alleles · common exomes 178,157/1,315,210 · genomes 21,615/152,302 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	21%	5
European (non-Finnish)grpmax	14.4%	7
Remaining individualsnot grpmax-eligible	12.9%	8
African / African-American	12.4%	8
South Asian	12.2%	8
Admixed American	10.4%	10
Ashkenazi Jewishnot grpmax-eligible	7.81%	13
Middle Eastern	7.69%	13
Amishnot grpmax-eligible	7.58%	13
East Asian	0.11%	907

Finnish 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: IQCE
Protein: p.Pro135=
Coding: c.405T>C
MANE Select: NM_152558
dbSNP: rs61739566
Type: single nucleotide variant
Location: chr7:2573428 (GRCh38)
Gene constraint: LOEUF 1.442 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.36

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

Disease context

polydactyly, postaxial, type a7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IQCE p.Pro135His Uncertain significance ★ ⚠ same residue
IQCE p.Met1Ile Likely pathogenic ★ same condition
IQCE p.Trp498Ter Pathogenic ★ same condition
IQCE p.Tyr255Ter Pathogenic ★ same condition
IQCE c.825-2A>G Uncertain significance ★ same condition
IQCE p.His615Tyr Uncertain significance ★ ⚠ same condition
IQCE c.1970-5T>C Benign ★ same condition
IQCE c.395-10G>C Benign ★ 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/iqce-p-pro135 (accessed [today's date]).

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