Is CHIT1 p.Ala39Pro (c.115G>C) pathogenic?

CHIT1 p.Ala39Pro (c.115G>C) is classified Uncertain significance in CHIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.2969); Very rare (popmax 0.000339%, nfe).

How common is CHIT1 p.Ala39Pro (c.115G>C) in the general population?

CHIT1 p.Ala39Pro (c.115G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CHIT1 p.Ala39Pro (c.115G>C)?

AlphaMissense predicts likely benign (score 0.2969) — an in-silico prediction, not a clinical call.

CHIT1 p.Ala39Pro

c.115G>C · rs774816645 · VCV3144366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2969	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -13.18	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP 0.9
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.56 · regional, not allelic
Overall
CADD	22.3	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 0.000339% European (non-Finnish) · 4/1,180,046 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00173% 28/1,614,084 alleles · very rare exomes 26/1,461,894 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,645
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)grpmax	0.000339%	295,011

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: CHIT1
Protein: p.Ala39Pro
Coding: c.115G>C
MANE Select: NM_003465
dbSNP: rs774816645
Type: single nucleotide variant
Location: chr1:203225811 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.72 · 23 PDB
Residue 39: the gh18 domain; an α-helix

Full CHIT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHIT1 p.Ala39Ser Benign ★ same residue
CHIT1 c.-13G>A Uncertain significance ★★ same type
CHIT1 c.*119C>T Uncertain significance ★★ same type
CHIT1 p.Arg128His Uncertain significance ★★ ⚠ same type
CHIT1 p.Arg432Trp Uncertain significance ★★ ⚠ same type
CHIT1 p.Pro451Arg Uncertain significance ★★ ⚠ same type
CHIT1 c.25+8G>T Likely benign ★★ same type
CHIT1 c.258-6T>C Benign ★★ 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/chit1-p-ala39pro (accessed [today's date]).

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