Is IQCE p.Pro658Ser (c.1972C>T) pathogenic?

IQCE p.Pro658Ser (c.1972C>T) is classified Likely benign in IQCE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-29). AlphaMissense: likely benign (0.067); Very rare (popmax 0.0022%, nfe).

How common is IQCE p.Pro658Ser (c.1972C>T) in the general population?

IQCE p.Pro658Ser (c.1972C>T) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about IQCE p.Pro658Ser (c.1972C>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

IQCE p.Pro658Ser

c.1972C>T · rs201192637 · VCV3110428

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.006	strongly benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.4	GERP 0.96
Regional constraint	o/e 1.15	unconstrained · MANE · 51 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	0.032	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 0.0022% European (non-Finnish) · 25/1,134,358 alleles

Filtering AF 0.00151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00166% 26/1,563,870 alleles · very rare exomes 22/1,411,780 · genomes 4/152,090 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,374
Remaining individualsnot grpmax-eligible	0.00164%	60,812

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.Pro658Ser
Coding: c.1972C>T
MANE Select: NM_152558
dbSNP: rs201192637
Type: single nucleotide variant
Location: chr7:2610046 (GRCh38)
Gene constraint: LOEUF 1.442 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.36
Residue 658: the 'disordered' region

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

Similar variants

IQCE p.Lys538Arg Uncertain significance ★★ ⚠ same type
IQCE p.Asp645= Benign/Likely benign ★★ same type
IQCE p.Leu277= Benign/Likely benign ★★ same type
IQCE p.Pro586Ser Likely benign ★★ same type
IQCE p.Met1Ile Likely pathogenic ★ same type
IQCE p.Trp498Ter Pathogenic ★ same type
IQCE p.Tyr255Ter Pathogenic ★ same type
IQCE c.1440+1G>T 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/iqce-p-pro658ser (accessed [today's date]).

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