Is LCT p.Ser991Phe (c.2972C>T) pathogenic?

LCT p.Ser991Phe (c.2972C>T) is classified Uncertain significance in LCT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.242); Very rare (popmax 0.00669%, eas); Associated with Inborn genetic diseases.

What condition is associated with LCT p.Ser991Phe (c.2972C>T)?

LCT p.Ser991Phe (c.2972C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LCT p.Ser991Phe (c.2972C>T) in the general population?

LCT p.Ser991Phe (c.2972C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about LCT p.Ser991Phe (c.2972C>T)?

AlphaMissense predicts likely benign (score 0.242) — an in-silico prediction, not a clinical call.

LCT p.Ser991Phe

c.2972C>T · VCV4623581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.242	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -12.83	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 5.2	GERP 0.95, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 5,551 bp · p 1.8e-08 · regional, not allelic
Overall
CADD	22.1	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 0.00669% East Asian · 3/44,876 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00041% 6/1,461,868 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,959
South Asian	0.0022%	45,545
African / African-American	0.00133%	75,048

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: LCT
Protein: p.Ser991Phe
Coding: c.2972C>T
MANE Select: NM_002299
Type: single nucleotide variant
Location: chr2:135809375 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 991: the 'glycosyl hydrolase-1 3; region iii. phlorizin hydrolase/glycosylceramidase activity' region

Full LCT 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

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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/lct-p-ser991phe (accessed [today's date]).

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