Is CHD7 p.Pro108His (c.323C>A) pathogenic?

CHD7 p.Pro108His (c.323C>A) is classified Conflicting classifications of pathogenicity in CHD7 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-11). AlphaMissense: likely benign (0.123); Ultra-rare (popmax 0.0164%, mid); Associated with CHARGE syndrome.

What condition is associated with CHD7 p.Pro108His (c.323C>A)?

CHD7 p.Pro108His (c.323C>A) is associated with CHARGE syndrome, hypogonadotropic hypogonadism 5 with or without anosmia (ClinVar).

How common is CHD7 p.Pro108His (c.323C>A) in the general population?

CHD7 p.Pro108His (c.323C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CHD7 p.Pro108His (c.323C>A)?

AlphaMissense predicts likely benign (score 0.123) — an in-silico prediction, not a clinical call.

CHD7 p.Pro108His

c.323C>A · rs369818702 · VCV195333

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

CHARGE syndrome

Computational evidence

Protein change
AlphaMissense	0.123	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00062% 10/1,613,840 alleles · ultra-rare exomes 9/1,461,614 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00167%	60,004
European (non-Finnish)	0.00017%	589,939

Ashkenazi Jewish 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: CHD7
Protein: p.Pro108His
Coding: c.323C>A
MANE Select: NM_017780
dbSNP: rs369818702
Type: single nucleotide variant
Location: chr8:60741755 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 108: the 'disordered' region

Full CHD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CHARGE syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypogonadotropic hypogonadism 5 with or without anosmia

Similar variants

CHD7 p.Pro108Ser Uncertain significance ★ ⚠ same residue
CHD7 p.Pro108Thr Uncertain significance ★ ⚠ same residue
CHD7 c.2097-2A>G Pathogenic ★★ same condition
CHD7 c.2238+1G>A Pathogenic ★★ same condition
CHD7 c.2377-1G>A Likely pathogenic ★★ same condition
CHD7 c.2613+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD7 c.2836-1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD7 c.2836-2A>T 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/chd7-p-pro108his (accessed [today's date]).

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