Is CLCN7 p.Ser91Phe (c.272C>T) pathogenic?

CLCN7 p.Ser91Phe (c.272C>T) is classified Uncertain significance in CLCN7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-01). AlphaMissense: likely pathogenic (0.9319); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with CLCN7 p.Ser91Phe (c.272C>T)?

CLCN7 p.Ser91Phe (c.272C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN7 p.Ser91Phe (c.272C>T) in the general population?

CLCN7 p.Ser91Phe (c.272C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CLCN7 p.Ser91Phe (c.272C>T)?

AlphaMissense predicts likely pathogenic (score 0.9319) — an in-silico prediction, not a clinical call.

CLCN7 p.Ser91Phe

c.272C>T · rs773700515 · VCV2174923

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9319	likely pathogenic
REVEL	0.744	pathogenic-leaning
SaProt	LLR -6.83	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 13 kb · p 0.031 · regional, not allelic
Overall
CADD	32.0	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 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00198% 32/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,700
Admixed Americangrpmax	0.00333%	30,003
European (non-Finnish)	0.00169%	59,001
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,930

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: CLCN7
Protein: p.Ser91Phe
Coding: c.272C>T
MANE Select: NM_001287
dbSNP: rs773700515
Type: single nucleotide variant
Location: chr16:1461616 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 9 PDB

Full CLCN7 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

CLCN7 p.Ser91= Likely benign ★ same residue
CLCN7 p.Ala131Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala195Ser Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala259Thr Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala464Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala673Val Uncertain significance ★★ ⚠ same condition
CLCN7 p.Ala714Thr Uncertain significance ★★ same condition
CLCN7 p.Arg223Trp 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/clcn7-p-ser91phe (accessed [today's date]).

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