Is HES7 p.Pro75Arg (c.224C>G) pathogenic?

HES7 p.Pro75Arg (c.224C>G) is classified Uncertain significance in HES7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1086); Very rare (popmax 0.00476%, sas); Associated with Inborn genetic diseases.

What condition is associated with HES7 p.Pro75Arg (c.224C>G)?

HES7 p.Pro75Arg (c.224C>G) is associated with Inborn genetic diseases (ClinVar).

How common is HES7 p.Pro75Arg (c.224C>G) in the general population?

HES7 p.Pro75Arg (c.224C>G) is very rare (popmax 0.00476%, sas) (gnomAD).

What do computational predictors say about HES7 p.Pro75Arg (c.224C>G)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

HES7 p.Pro75Arg

c.224C>G · rs768825167 · VCV2604419

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00476%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -8.18	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 6.3	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 2,510 bp · p 0.41 · regional, not allelic
Overall
CADD	26.0	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 0.00476% South Asian · 4/84,032 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000949%

Overall 0.000427% 6/1,406,124 alleles · very rare exomes 6/1,259,120 · genomes 0/147,004 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00476%	21,008
European (non-Finnish)	0.000194%	515,719

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: HES7
Protein: p.Pro75Arg
Coding: c.224C>G
MANE Select: NM_001165967
dbSNP: rs768825167
Type: single nucleotide variant
Location: chr17:8122345 (GRCh38)
Gene constraint: LOEUF 1.319 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.31

Full HES7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HES7 p.Pro75= Uncertain significance ★ same residue
HES7 p.Ala109Glu Uncertain significance ★★ ⚠ same condition
HES7 p.Ala126Gly Uncertain significance ★★ ⚠ same condition
HES7 p.Arg227Ser Uncertain significance ★★ ⚠ same condition
HES7 p.Arg30Ser Uncertain significance ★★ ⚠ same condition
HES7 p.Asp142Tyr Uncertain significance ★★ ⚠ same condition
HES7 p.Leu19Val Uncertain significance ★★ ⚠ same condition
HES7 p.Leu40Pro Uncertain significance ★★ ⚠ 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/hes7-p-pro75arg (accessed [today's date]).

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